Links to Exploration step
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Immunotherapy of distant metastatic disease</title><author><name sortKey="Schadendorf, D" sort="Schadendorf, D" uniqKey="Schadendorf D" first="D." last="Schadendorf">D. Schadendorf</name><affiliation><nlm:aff id="aff1">Department of Dermatology, University Hospital Essen, Essen, Germany</nlm:aff></affiliation></author><author><name sortKey="Algarra, S M" sort="Algarra, S M" uniqKey="Algarra S" first="S. M." last="Algarra">S. M. Algarra</name><affiliation><nlm:aff id="aff2">Department of Oncology, Clinica Universitaria de Navarra, Pamplona, Spain</nlm:aff></affiliation></author><author><name sortKey="Bastholt, L" sort="Bastholt, L" uniqKey="Bastholt L" first="L." last="Bastholt">L. Bastholt</name><affiliation><nlm:aff id="aff3">Department of Oncology, Odense University Hospital, Odense, Denmark</nlm:aff></affiliation></author><author><name sortKey="Cinat, G" sort="Cinat, G" uniqKey="Cinat G" first="G." last="Cinat">G. Cinat</name><affiliation><nlm:aff id="aff4">Department of Oncology, Instituto de Oncologia Angel Roffo, Buenos Aires, Argentina</nlm:aff></affiliation></author><author><name sortKey="Dreno, B" sort="Dreno, B" uniqKey="Dreno B" first="B." last="Dreno">B. Dreno</name><affiliation><nlm:aff id="aff5">Clinique of Dermatologie, Hôtel Dieu, Nantes Cedex 01, France</nlm:aff></affiliation></author><author><name sortKey="Eggermont, A M M" sort="Eggermont, A M M" uniqKey="Eggermont A" first="A. M. M." last="Eggermont">A. M. M. Eggermont</name><affiliation><nlm:aff id="aff6">Department of Surgical Oncology, Erasmus University Medical Center–Daniel den Hoed Cancer Center, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Espinosa, E" sort="Espinosa, E" uniqKey="Espinosa E" first="E." last="Espinosa">E. Espinosa</name><affiliation><nlm:aff id="aff7">Department of Oncology, Hospital La Paz, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Guo, J" sort="Guo, J" uniqKey="Guo J" first="J." last="Guo">J. Guo</name><affiliation><nlm:aff id="aff8">Department of Oncology, Peking University School of Oncology, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Hauschild, A" sort="Hauschild, A" uniqKey="Hauschild A" first="A." last="Hauschild">A. Hauschild</name><affiliation><nlm:aff id="aff9">Department of Dermatology, University of Kiel, Kiel, Germany</nlm:aff></affiliation></author><author><name sortKey="Petrella, T" sort="Petrella, T" uniqKey="Petrella T" first="T." last="Petrella">T. Petrella</name><affiliation><nlm:aff id="aff10">Toronto Sunnybrook Regional Cancer Center, Toronto, Canada</nlm:aff></affiliation></author><author><name sortKey="Schachter, J" sort="Schachter, J" uniqKey="Schachter J" first="J." last="Schachter">J. Schachter</name><affiliation><nlm:aff id="aff11">The Ella Institute for Treatment and Research of Melanoma, Tel Hashomer, Israel</nlm:aff></affiliation></author><author><name sortKey="Hersey, P" sort="Hersey, P" uniqKey="Hersey P" first="P." last="Hersey">P. Hersey</name><affiliation><nlm:aff id="aff12">Immunology and Oncology Unit, Calvary Mater Newcastle Hospital, New South Wales, Australia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">19617297</idno><idno type="pmc">2712591</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712591</idno><idno type="RBID">PMC:2712591</idno><idno type="doi">10.1093/annonc/mdp253</idno><date when="2009">2009</date><idno type="wicri:Area/Pmc/Corpus">002241</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002241</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Immunotherapy of distant metastatic disease</title><author><name sortKey="Schadendorf, D" sort="Schadendorf, D" uniqKey="Schadendorf D" first="D." last="Schadendorf">D. Schadendorf</name><affiliation><nlm:aff id="aff1">Department of Dermatology, University Hospital Essen, Essen, Germany</nlm:aff></affiliation></author><author><name sortKey="Algarra, S M" sort="Algarra, S M" uniqKey="Algarra S" first="S. M." last="Algarra">S. M. Algarra</name><affiliation><nlm:aff id="aff2">Department of Oncology, Clinica Universitaria de Navarra, Pamplona, Spain</nlm:aff></affiliation></author><author><name sortKey="Bastholt, L" sort="Bastholt, L" uniqKey="Bastholt L" first="L." last="Bastholt">L. Bastholt</name><affiliation><nlm:aff id="aff3">Department of Oncology, Odense University Hospital, Odense, Denmark</nlm:aff></affiliation></author><author><name sortKey="Cinat, G" sort="Cinat, G" uniqKey="Cinat G" first="G." last="Cinat">G. Cinat</name><affiliation><nlm:aff id="aff4">Department of Oncology, Instituto de Oncologia Angel Roffo, Buenos Aires, Argentina</nlm:aff></affiliation></author><author><name sortKey="Dreno, B" sort="Dreno, B" uniqKey="Dreno B" first="B." last="Dreno">B. Dreno</name><affiliation><nlm:aff id="aff5">Clinique of Dermatologie, Hôtel Dieu, Nantes Cedex 01, France</nlm:aff></affiliation></author><author><name sortKey="Eggermont, A M M" sort="Eggermont, A M M" uniqKey="Eggermont A" first="A. M. M." last="Eggermont">A. M. M. Eggermont</name><affiliation><nlm:aff id="aff6">Department of Surgical Oncology, Erasmus University Medical Center–Daniel den Hoed Cancer Center, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Espinosa, E" sort="Espinosa, E" uniqKey="Espinosa E" first="E." last="Espinosa">E. Espinosa</name><affiliation><nlm:aff id="aff7">Department of Oncology, Hospital La Paz, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Guo, J" sort="Guo, J" uniqKey="Guo J" first="J." last="Guo">J. Guo</name><affiliation><nlm:aff id="aff8">Department of Oncology, Peking University School of Oncology, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Hauschild, A" sort="Hauschild, A" uniqKey="Hauschild A" first="A." last="Hauschild">A. Hauschild</name><affiliation><nlm:aff id="aff9">Department of Dermatology, University of Kiel, Kiel, Germany</nlm:aff></affiliation></author><author><name sortKey="Petrella, T" sort="Petrella, T" uniqKey="Petrella T" first="T." last="Petrella">T. Petrella</name><affiliation><nlm:aff id="aff10">Toronto Sunnybrook Regional Cancer Center, Toronto, Canada</nlm:aff></affiliation></author><author><name sortKey="Schachter, J" sort="Schachter, J" uniqKey="Schachter J" first="J." last="Schachter">J. Schachter</name><affiliation><nlm:aff id="aff11">The Ella Institute for Treatment and Research of Melanoma, Tel Hashomer, Israel</nlm:aff></affiliation></author><author><name sortKey="Hersey, P" sort="Hersey, P" uniqKey="Hersey P" first="P." last="Hersey">P. Hersey</name><affiliation><nlm:aff id="aff12">Immunology and Oncology Unit, Calvary Mater Newcastle Hospital, New South Wales, Australia</nlm:aff></affiliation></author></analytic><series><title level="j">Annals of Oncology</title><idno type="ISSN">0923-7534</idno><idno type="eISSN">1569-8041</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Immunotherapy of metastatic melanoma consists of various approaches leading to specific or non-specific immunomodulation. The use of FDA-approved interleukin (IL)-2 alone, in combination with interferon α, and/or with various chemotherapeutic agents (biochemotherapy) is associated with significant toxicity and poor efficacy that does not improve overall survival of 96% of patients. Many studies with allogeneic and autologous vaccines have demonstrated no clinical benefit, and some randomised trials even showed a detrimental effect in the vaccine arm. The ongoing effort to develop melanoma vaccines based on dendritic cells and peptides is driven by advances in understanding antigen presentation and processing, and by new techniques of vaccine preparation, stabilisation and delivery. Several agents that have shown promising activity in metastatic melanoma including IL-21 and monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) or CD137 are discussed. Recent advances of intratumour gene transfer technologies and adoptive immunotherapy, which represents a promising although technically challenging direction, are also discussed.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Balch, Cm" uniqKey="Balch C">CM Balch</name></author><author><name sortKey="Buzaid, Ac" uniqKey="Buzaid A">AC Buzaid</name></author><author><name sortKey="Soong, Sj" uniqKey="Soong S">SJ Soong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Atkins, Mb" uniqKey="Atkins M">MB Atkins</name></author><author><name sortKey="Lotze, Mt" uniqKey="Lotze M">MT Lotze</name></author><author><name sortKey="Dutcher, Jp" uniqKey="Dutcher J">JP Dutcher</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tsao, H" uniqKey="Tsao H">H Tsao</name></author><author><name sortKey="Atkins, Mb" uniqKey="Atkins M">MB Atkins</name></author><author><name sortKey="Sober, Aj" uniqKey="Sober A">AJ Sober</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Keilholz, U" uniqKey="Keilholz U">U Keilholz</name></author><author><name sortKey="Conradt, C" uniqKey="Conradt C">C Conradt</name></author><author><name sortKey="Legha, Ss" uniqKey="Legha S">SS Legha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Phan, Gq" uniqKey="Phan G">GQ Phan</name></author><author><name sortKey="Attia, P" uniqKey="Attia P">P Attia</name></author><author><name sortKey="Steinberg, Sm" uniqKey="Steinberg S">SM Steinberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schmidt, H" uniqKey="Schmidt H">H Schmidt</name></author><author><name sortKey="Bastholt, L" uniqKey="Bastholt L">L Bastholt</name></author><author><name sortKey="Geertsen, P" uniqKey="Geertsen P">P Geertsen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schmidt, H" uniqKey="Schmidt H">H Schmidt</name></author><author><name sortKey="Suciu, S" uniqKey="Suciu S">S Suciu</name></author><author><name sortKey="Punt, Cj" uniqKey="Punt C">CJ Punt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tarhini, Aa" uniqKey="Tarhini A">AA Tarhini</name></author><author><name sortKey="Kirkwood, Jm" uniqKey="Kirkwood J">JM Kirkwood</name></author><author><name sortKey="Gooding, We" uniqKey="Gooding W">WE Gooding</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Petrella, T" uniqKey="Petrella T">T Petrella</name></author><author><name sortKey="Quirt, I" uniqKey="Quirt I">I Quirt</name></author><author><name sortKey="Verma, S" uniqKey="Verma S">S Verma</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Legha, Ss" uniqKey="Legha S">SS Legha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bukowski, Rm" uniqKey="Bukowski R">RM Bukowski</name></author><author><name sortKey="Tendler, C" uniqKey="Tendler C">C Tendler</name></author><author><name sortKey="Cutler, D" uniqKey="Cutler D">D Cutler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dummer, R" uniqKey="Dummer R">R Dummer</name></author><author><name sortKey="Garbe, C" uniqKey="Garbe C">C Garbe</name></author><author><name sortKey="Thompson, Ja" uniqKey="Thompson J">JA Thompson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hauschild, A" uniqKey="Hauschild A">A Hauschild</name></author><author><name sortKey="Dummer, R" uniqKey="Dummer R">R Dummer</name></author><author><name sortKey="Ugurel, S" uniqKey="Ugurel S">S Ugurel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Spieth, K" uniqKey="Spieth K">K Spieth</name></author><author><name sortKey="Kaufmann, R" uniqKey="Kaufmann R">R Kaufmann</name></author><author><name sortKey="Dummer, R" uniqKey="Dummer R">R Dummer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sparano, Ja" uniqKey="Sparano J">JA Sparano</name></author><author><name sortKey="Fisher, Ri" uniqKey="Fisher R">RI Fisher</name></author><author><name sortKey="Sunderland, M" uniqKey="Sunderland M">M Sunderland</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Marincola, Fm" uniqKey="Marincola F">FM Marincola</name></author><author><name sortKey="White, De" uniqKey="White D">DE White</name></author><author><name sortKey="Wise, Ap" uniqKey="Wise A">AP Wise</name></author><author><name sortKey="Rosenberg, Sa" uniqKey="Rosenberg S">SA Rosenberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hamm, C" uniqKey="Hamm C">C Hamm</name></author><author><name sortKey="Verma, S" uniqKey="Verma S">S Verma</name></author><author><name sortKey="Petrella, T" uniqKey="Petrella T">T Petrella</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ives, Nj" uniqKey="Ives N">NJ Ives</name></author><author><name sortKey="Stowe, Rl" uniqKey="Stowe R">RL Stowe</name></author><author><name sortKey="Lorigan, P" uniqKey="Lorigan P">P Lorigan</name></author><author><name sortKey="Wheatley, K" uniqKey="Wheatley K">K Wheatley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Falkson, Ci" uniqKey="Falkson C">CI Falkson</name></author><author><name sortKey="Falkson, G" uniqKey="Falkson G">G Falkson</name></author><author><name sortKey="Falkson, Hc" uniqKey="Falkson H">HC Falkson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thomson, Db" uniqKey="Thomson D">DB Thomson</name></author><author><name sortKey="Adena, M" uniqKey="Adena M">M Adena</name></author><author><name sortKey="Mcleod, Gr" uniqKey="Mcleod G">GR McLeod</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bajetta, E" uniqKey="Bajetta E">E Bajetta</name></author><author><name sortKey="Di Leo, A" uniqKey="Di Leo A">A Di Leo</name></author><author><name sortKey="Zampino, Mg" uniqKey="Zampino M">MG Zampino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Falkson, Ci" uniqKey="Falkson C">CI Falkson</name></author><author><name sortKey="Ibrahim, J" uniqKey="Ibrahim J">J Ibrahim</name></author><author><name sortKey="Kirkwood, Jm" uniqKey="Kirkwood J">JM Kirkwood</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Middleton, Mr" uniqKey="Middleton M">MR Middleton</name></author><author><name sortKey="Lorigan, P" uniqKey="Lorigan P">P Lorigan</name></author><author><name sortKey="Owen, J" uniqKey="Owen J">J Owen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Young, Am" uniqKey="Young A">AM Young</name></author><author><name sortKey="Marsden, J" uniqKey="Marsden J">J Marsden</name></author><author><name sortKey="Goodman, A" uniqKey="Goodman A">A Goodman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kaufmann, R" uniqKey="Kaufmann R">R Kaufmann</name></author><author><name sortKey="Spieth, K" uniqKey="Spieth K">K Spieth</name></author><author><name sortKey="Leiter, U" uniqKey="Leiter U">U Leiter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vuoristo, Ms" uniqKey="Vuoristo M">MS Vuoristo</name></author><author><name sortKey="Hahka Kemppinen, M" uniqKey="Hahka Kemppinen M">M Hahka-Kemppinen</name></author><author><name sortKey="Parvinen, Lm" uniqKey="Parvinen L">LM Parvinen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Agarwala, Ss" uniqKey="Agarwala S">SS Agarwala</name></author><author><name sortKey="Glaspy, J" uniqKey="Glaspy J">J Glaspy</name></author><author><name sortKey="O Day, Sj" uniqKey="O Day S">SJ O'Day</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Keilholz, U" uniqKey="Keilholz U">U Keilholz</name></author><author><name sortKey="Goey, Sh" uniqKey="Goey S">SH Goey</name></author><author><name sortKey="Punt, Cj" uniqKey="Punt C">CJ Punt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Johnston, Sr" uniqKey="Johnston S">SR Johnston</name></author><author><name sortKey="Constenla, Do" uniqKey="Constenla D">DO Constenla</name></author><author><name sortKey="Moore, J" uniqKey="Moore J">J Moore</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dorval, T" uniqKey="Dorval T">T Dorval</name></author><author><name sortKey="Negrier, S" uniqKey="Negrier S">S Negrier</name></author><author><name sortKey="Chevreau, C" uniqKey="Chevreau C">C Chevreau</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rosenberg, Sa" uniqKey="Rosenberg S">SA Rosenberg</name></author><author><name sortKey="Yang, Jc" uniqKey="Yang J">JC Yang</name></author><author><name sortKey="Schwartzentruber, Dj" uniqKey="Schwartzentruber D">DJ Schwartzentruber</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hauschild, A" uniqKey="Hauschild A">A Hauschild</name></author><author><name sortKey="Garbe, C" uniqKey="Garbe C">C Garbe</name></author><author><name sortKey="Stolz, W" uniqKey="Stolz W">W Stolz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Eton, O" uniqKey="Eton O">O Eton</name></author><author><name sortKey="Legha, Ss" uniqKey="Legha S">SS Legha</name></author><author><name sortKey="Bedikian, Ay" uniqKey="Bedikian A">AY Bedikian</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Atzpodien, J" uniqKey="Atzpodien J">J Atzpodien</name></author><author><name sortKey="Neuber, K" uniqKey="Neuber K">K Neuber</name></author><author><name sortKey="Kamanabrou, D" uniqKey="Kamanabrou D">D Kamanabrou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ridolfi, R" uniqKey="Ridolfi R">R Ridolfi</name></author><author><name sortKey="Chiarion Sileni, V" uniqKey="Chiarion Sileni V">V Chiarion-Sileni</name></author><author><name sortKey="Guida, M" uniqKey="Guida M">M Guida</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Keilholz, U" uniqKey="Keilholz U">U Keilholz</name></author><author><name sortKey="Punt, Cj" uniqKey="Punt C">CJ Punt</name></author><author><name sortKey="Gore, M" uniqKey="Gore M">M Gore</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bajetta, E" uniqKey="Bajetta E">E Bajetta</name></author><author><name sortKey="Del Vecchio, M" uniqKey="Del Vecchio M">M Del Vecchio</name></author><author><name sortKey="Nova, P" uniqKey="Nova P">P Nova</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Atkins, Mb" uniqKey="Atkins M">MB Atkins</name></author><author><name sortKey="Hsu, J" uniqKey="Hsu J">J Hsu</name></author><author><name sortKey="Lee, S" uniqKey="Lee S">S Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Davis, Id" uniqKey="Davis I">ID Davis</name></author><author><name sortKey="Skak, K" uniqKey="Skak K">K Skak</name></author><author><name sortKey="Smyth, Mj" uniqKey="Smyth M">MJ Smyth</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fehniger, Ta" uniqKey="Fehniger T">TA Fehniger</name></author><author><name sortKey="Cooper, Ma" uniqKey="Cooper M">MA Cooper</name></author><author><name sortKey="Caligiuri, Ma" uniqKey="Caligiuri M">MA Caligiuri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thompson, Ja" uniqKey="Thompson J">JA Thompson</name></author><author><name sortKey="Curti, Bd" uniqKey="Curti B">BD Curti</name></author><author><name sortKey="Redman, Bg" uniqKey="Redman B">BG Redman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Frederiksen, Ks" uniqKey="Frederiksen K">KS Frederiksen</name></author><author><name sortKey="Lundsgaard, D" uniqKey="Lundsgaard D">D Lundsgaard</name></author><author><name sortKey="Freeman, Ja" uniqKey="Freeman J">JA Freeman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Inman, Ba" uniqKey="Inman B">BA Inman</name></author><author><name sortKey="Frigola, X" uniqKey="Frigola X">X Frigola</name></author><author><name sortKey="Dong, H" uniqKey="Dong H">H Dong</name></author><author><name sortKey="Kwon, Ed" uniqKey="Kwon E">ED Kwon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Melero, I" uniqKey="Melero I">I Melero</name></author><author><name sortKey="Hervas Stubbs, S" uniqKey="Hervas Stubbs S">S Hervas-Stubbs</name></author><author><name sortKey="Glennie, M" uniqKey="Glennie M">M Glennie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="O Day, Sj" uniqKey="O Day S">SJ O'Day</name></author><author><name sortKey="Hamid, O" uniqKey="Hamid O">O Hamid</name></author><author><name sortKey="Urba, Wj" uniqKey="Urba W">WJ Urba</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cranmer, Ld" uniqKey="Cranmer L">LD Cranmer</name></author><author><name sortKey="Hersh, E" uniqKey="Hersh E">E Hersh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Weber, J" uniqKey="Weber J">J Weber</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ribas, A" uniqKey="Ribas A">A Ribas</name></author><author><name sortKey="Hanson, Dc" uniqKey="Hanson D">DC Hanson</name></author><author><name sortKey="Noe, Da" uniqKey="Noe D">DA Noe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hersh, Em" uniqKey="Hersh E">EM Hersh</name></author><author><name sortKey="Weber, Js" uniqKey="Weber J">JS Weber</name></author><author><name sortKey="Powderly, Jd" uniqKey="Powderly J">JD Powderly</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Attia, P" uniqKey="Attia P">P Attia</name></author><author><name sortKey="Phan, Gq" uniqKey="Phan G">GQ Phan</name></author><author><name sortKey="Maker, Av" uniqKey="Maker A">AV Maker</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Downey, Sg" uniqKey="Downey S">SG Downey</name></author><author><name sortKey="Klapper, Ja" uniqKey="Klapper J">JA Klapper</name></author><author><name sortKey="Smith, Fo" uniqKey="Smith F">FO Smith</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Beck, Ke" uniqKey="Beck K">KE Beck</name></author><author><name sortKey="Blansfield, Ja" uniqKey="Blansfield J">JA Blansfield</name></author><author><name sortKey="Tran, Kq" uniqKey="Tran K">KQ Tran</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hamid, O" uniqKey="Hamid O">O Hamid</name></author><author><name sortKey="Chin, K" uniqKey="Chin K">K Chin</name></author><author><name sortKey="Li, J" uniqKey="Li J">J Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="O Day, Sj" uniqKey="O Day S">SJ O'Day</name></author><author><name sortKey="Ibrahim, R" uniqKey="Ibrahim R">R Ibrahim</name></author><author><name sortKey="Depril, V" uniqKey="Depril V">V DePril</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wolchok, Jd" uniqKey="Wolchok J">JD Wolchok</name></author><author><name sortKey="Ibrahim, R" uniqKey="Ibrahim R">R Ibrahim</name></author><author><name sortKey="Depril, V" uniqKey="Depril V">V DePril</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hodi, Fs" uniqKey="Hodi F">FS Hodi</name></author><author><name sortKey="Hoos, A" uniqKey="Hoos A">A Hoos</name></author><author><name sortKey="Ibrahim, R" uniqKey="Ibrahim R">R Ibrahim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ribas, A" uniqKey="Ribas A">A Ribas</name></author><author><name sortKey="Antonia, S" uniqKey="Antonia S">S Antonia</name></author><author><name sortKey="Sosman, J" uniqKey="Sosman J">J Sosman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gomez Navarro, J" uniqKey="Gomez Navarro J">J Gomez-Navarro</name></author><author><name sortKey="Antonia, S" uniqKey="Antonia S">S Antonia</name></author><author><name sortKey="Sosman, J" uniqKey="Sosman J">J Sosman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kirkwood, Jm" uniqKey="Kirkwood J">JM Kirkwood</name></author><author><name sortKey="Lorigan, P" uniqKey="Lorigan P">P Lorigan</name></author><author><name sortKey="Hersey, P" uniqKey="Hersey P">P Hersey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ribas, A" uniqKey="Ribas A">A Ribas</name></author><author><name sortKey="Hauschild, A" uniqKey="Hauschild A">A Hauschild</name></author><author><name sortKey="Kefford, R" uniqKey="Kefford R">R Kefford</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tarhini, Aa" uniqKey="Tarhini A">AA Tarhini</name></author><author><name sortKey="Moschos, Ss" uniqKey="Moschos S">SS Moschos</name></author><author><name sortKey="Schlesselman, Jj" uniqKey="Schlesselman J">JJ Schlesselman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, B" uniqKey="Li B">B Li</name></author><author><name sortKey="Lin, J" uniqKey="Lin J">J Lin</name></author><author><name sortKey="Vanroey, M" uniqKey="Vanroey M">M Vanroey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Choi, Bk" uniqKey="Choi B">BK Choi</name></author><author><name sortKey="Kim, Yh" uniqKey="Kim Y">YH Kim</name></author><author><name sortKey="Kang, Wj" uniqKey="Kang W">WJ Kang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sznol, M" uniqKey="Sznol M">M Sznol</name></author><author><name sortKey="Hodi, Fs" uniqKey="Hodi F">FS Hodi</name></author><author><name sortKey="Margolin, K" uniqKey="Margolin K">K Margolin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Trikha, M" uniqKey="Trikha M">M Trikha</name></author><author><name sortKey="Zhou, Z" uniqKey="Zhou Z">Z Zhou</name></author><author><name sortKey="Nemeth, Ja" uniqKey="Nemeth J">JA Nemeth</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jayson, Gc" uniqKey="Jayson G">GC Jayson</name></author><author><name sortKey="Mullamitha, S" uniqKey="Mullamitha S">S Mullamitha</name></author><author><name sortKey="Ton, C" uniqKey="Ton C">C Ton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cranmer, Ld" uniqKey="Cranmer L">LD Cranmer</name></author><author><name sortKey="Bedikian, Ay" uniqKey="Bedikian A">AY Bedikian</name></author><author><name sortKey="Ribas, A" uniqKey="Ribas A">A Ribas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Linette, G" uniqKey="Linette G">G Linette</name></author><author><name sortKey="Cranmer, L" uniqKey="Cranmer L">L Cranmer</name></author><author><name sortKey="Hodi, S" uniqKey="Hodi S">S Hodi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mulgrew, K" uniqKey="Mulgrew K">K Mulgrew</name></author><author><name sortKey="Kinneer, K" uniqKey="Kinneer K">K Kinneer</name></author><author><name sortKey="Yao, Xt" uniqKey="Yao X">XT Yao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hersey, P" uniqKey="Hersey P">P Hersey</name></author><author><name sortKey="Sosman, J" uniqKey="Sosman J">J Sosman</name></author><author><name sortKey="O Day, S" uniqKey="O Day S">S O'Day</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rosenberg, Sa" uniqKey="Rosenberg S">SA Rosenberg</name></author><author><name sortKey="Yang, Jc" uniqKey="Yang J">JC Yang</name></author><author><name sortKey="Restifo, Np" uniqKey="Restifo N">NP Restifo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sondak, Vk" uniqKey="Sondak V">VK Sondak</name></author><author><name sortKey="Sabel, Ms" uniqKey="Sabel M">MS Sabel</name></author><author><name sortKey="Mule, Jj" uniqKey="Mule J">JJ Mule</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morton, Dl" uniqKey="Morton D">DL Morton</name></author><author><name sortKey="Mozzillo, N" uniqKey="Mozzillo N">N Mozzillo</name></author><author><name sortKey="Thompson, Jf" uniqKey="Thompson J">JF Thompson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Srivastava, P" uniqKey="Srivastava P">P Srivastava</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Belli, F" uniqKey="Belli F">F Belli</name></author><author><name sortKey="Testori, A" uniqKey="Testori A">A Testori</name></author><author><name sortKey="Rivoltini, L" uniqKey="Rivoltini L">L Rivoltini</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Testori, A" uniqKey="Testori A">A Testori</name></author><author><name sortKey="Richards, J" uniqKey="Richards J">J Richards</name></author><author><name sortKey="Whitman, E" uniqKey="Whitman E">E Whitman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Coulie, Pg" uniqKey="Coulie P">PG Coulie</name></author><author><name sortKey="Karanikas, V" uniqKey="Karanikas V">V Karanikas</name></author><author><name sortKey="Colau, D" uniqKey="Colau D">D Colau</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kruit, Wh" uniqKey="Kruit W">WH Kruit</name></author><author><name sortKey="Suciu, S" uniqKey="Suciu S">S Suciu</name></author><author><name sortKey="Dreno, B" uniqKey="Dreno B">B Dreno</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Purcell, Aw" uniqKey="Purcell A">AW Purcell</name></author><author><name sortKey="Mccluskey, J" uniqKey="Mccluskey J">J McCluskey</name></author><author><name sortKey="Rossjohn, J" uniqKey="Rossjohn J">J Rossjohn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Melief, Cj" uniqKey="Melief C">CJ Melief</name></author><author><name sortKey="Van Der Burg, Sh" uniqKey="Van Der Burg S">SH van der Burg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Osada, T" uniqKey="Osada T">T Osada</name></author><author><name sortKey="Clay, Tm" uniqKey="Clay T">TM Clay</name></author><author><name sortKey="Woo, Cy" uniqKey="Woo C">CY Woo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thurner, B" uniqKey="Thurner B">B Thurner</name></author><author><name sortKey="Haendle, I" uniqKey="Haendle I">I Haendle</name></author><author><name sortKey="Roder, C" uniqKey="Roder C">C Roder</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schadendorf, D" uniqKey="Schadendorf D">D Schadendorf</name></author><author><name sortKey="Ugurel, S" uniqKey="Ugurel S">S Ugurel</name></author><author><name sortKey="Schuler Thurner, B" uniqKey="Schuler Thurner B">B Schuler-Thurner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lesterhuis, Wj" uniqKey="Lesterhuis W">WJ Lesterhuis</name></author><author><name sortKey="Aarntzen, Eh" uniqKey="Aarntzen E">EH Aarntzen</name></author><author><name sortKey="De Vries, Ij" uniqKey="De Vries I">IJ De Vries</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lens, M" uniqKey="Lens M">M Lens</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dummer, R" uniqKey="Dummer R">R Dummer</name></author><author><name sortKey="Rochlitz, C" uniqKey="Rochlitz C">C Rochlitz</name></author><author><name sortKey="Velu, T" uniqKey="Velu T">T Velu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Heinzerling, L" uniqKey="Heinzerling L">L Heinzerling</name></author><author><name sortKey="Burg, G" uniqKey="Burg G">G Burg</name></author><author><name sortKey="Dummer, R" uniqKey="Dummer R">R Dummer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mahvi, Dm" uniqKey="Mahvi D">DM Mahvi</name></author><author><name sortKey="Henry, Mb" uniqKey="Henry M">MB Henry</name></author><author><name sortKey="Albertini, Mr" uniqKey="Albertini M">MR Albertini</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Senzer, Nn" uniqKey="Senzer N">NN Senzer</name></author><author><name sortKey="Kaufman, Hl" uniqKey="Kaufman H">HL Kaufman</name></author><author><name sortKey="Amatruda, T" uniqKey="Amatruda T">T Amatruda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gattinoni, L" uniqKey="Gattinoni L">L Gattinoni</name></author><author><name sortKey="Powell, Dj" uniqKey="Powell D">DJ Powell</name></author><author><name sortKey="Rosenberg, Sa" uniqKey="Rosenberg S">SA Rosenberg</name></author><author><name sortKey="Restifo, Np" uniqKey="Restifo N">NP Restifo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mule, Jj" uniqKey="Mule J">JJ Mule</name></author><author><name sortKey="Shu, S" uniqKey="Shu S">S Shu</name></author><author><name sortKey="Schwarz, Sl" uniqKey="Schwarz S">SL Schwarz</name></author><author><name sortKey="Rosenberg, Sa" uniqKey="Rosenberg S">SA Rosenberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rosenberg, Sa" uniqKey="Rosenberg S">SA Rosenberg</name></author><author><name sortKey="Spiess, P" uniqKey="Spiess P">P Spiess</name></author><author><name sortKey="Lafreniere, R" uniqKey="Lafreniere R">R Lafreniere</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rosenberg, Sa" uniqKey="Rosenberg S">SA Rosenberg</name></author><author><name sortKey="Yannelli, Jr" uniqKey="Yannelli J">JR Yannelli</name></author><author><name sortKey="Yang, Jc" uniqKey="Yang J">JC Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dudley, Me" uniqKey="Dudley M">ME Dudley</name></author><author><name sortKey="Wunderlich, Jr" uniqKey="Wunderlich J">JR Wunderlich</name></author><author><name sortKey="Robbins, Pf" uniqKey="Robbins P">PF Robbins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mackensen, A" uniqKey="Mackensen A">A Mackensen</name></author><author><name sortKey="Meidenbauer, N" uniqKey="Meidenbauer N">N Meidenbauer</name></author><author><name sortKey="Vogl, S" uniqKey="Vogl S">S Vogl</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Powell, Dj" uniqKey="Powell D">DJ Powell</name></author><author><name sortKey="Dudley, Me" uniqKey="Dudley M">ME Dudley</name></author><author><name sortKey="Hogan, Ka" uniqKey="Hogan K">KA Hogan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hunder, Nn" uniqKey="Hunder N">NN Hunder</name></author><author><name sortKey="Wallen, H" uniqKey="Wallen H">H Wallen</name></author><author><name sortKey="Cao, J" uniqKey="Cao J">J Cao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dudley, Me" uniqKey="Dudley M">ME Dudley</name></author><author><name sortKey="Wunderlich, Jr" uniqKey="Wunderlich J">JR Wunderlich</name></author><author><name sortKey="Yang, Jc" uniqKey="Yang J">JC Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rosenberg, Sa" uniqKey="Rosenberg S">SA Rosenberg</name></author><author><name sortKey="Restifo, Np" uniqKey="Restifo N">NP Restifo</name></author><author><name sortKey="Yang, Jc" uniqKey="Yang J">JC Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morgan, Ra" uniqKey="Morgan R">RA Morgan</name></author><author><name sortKey="Dudley, Me" uniqKey="Dudley M">ME Dudley</name></author><author><name sortKey="Wunderlich, Jr" uniqKey="Wunderlich J">JR Wunderlich</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tran, Kq" uniqKey="Tran K">KQ Tran</name></author><author><name sortKey="Zhou, J" uniqKey="Zhou J">J Zhou</name></author><author><name sortKey="Durflinger, Kh" uniqKey="Durflinger K">KH Durflinger</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Ann Oncol</journal-id><journal-id journal-id-type="iso-abbrev">Ann. Oncol</journal-id><journal-id journal-id-type="hwp">annonc</journal-id><journal-id journal-id-type="publisher-id">annonc</journal-id><journal-title-group><journal-title>Annals of Oncology</journal-title></journal-title-group><issn pub-type="ppub">0923-7534</issn><issn pub-type="epub">1569-8041</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">19617297</article-id><article-id pub-id-type="pmc">2712591</article-id><article-id pub-id-type="doi">10.1093/annonc/mdp253</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>Immunotherapy of distant metastatic disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Schadendorf</surname><given-names>D.</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Algarra</surname><given-names>S. M.</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Bastholt</surname><given-names>L.</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Cinat</surname><given-names>G.</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Dreno</surname><given-names>B.</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Eggermont</surname><given-names>A. M. M.</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Espinosa</surname><given-names>E.</given-names></name><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Guo</surname><given-names>J.</given-names></name><xref ref-type="aff" rid="aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Hauschild</surname><given-names>A.</given-names></name><xref ref-type="aff" rid="aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Petrella</surname><given-names>T.</given-names></name><xref ref-type="aff" rid="aff10">10</xref></contrib><contrib contrib-type="author"><name><surname>Schachter</surname><given-names>J.</given-names></name><xref ref-type="aff" rid="aff11">11</xref></contrib><contrib contrib-type="author"><name><surname>Hersey</surname><given-names>P.</given-names></name><xref ref-type="aff" rid="aff12">12</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Department of Dermatology, University Hospital Essen, Essen, Germany</aff><aff id="aff2"><label>2</label>Department of Oncology, Clinica Universitaria de Navarra, Pamplona, Spain</aff><aff id="aff3"><label>3</label>Department of Oncology, Odense University Hospital, Odense, Denmark</aff><aff id="aff4"><label>4</label>Department of Oncology, Instituto de Oncologia Angel Roffo, Buenos Aires, Argentina</aff><aff id="aff5"><label>5</label>Clinique of Dermatologie, Hôtel Dieu, Nantes Cedex 01, France</aff><aff id="aff6"><label>6</label>Department of Surgical Oncology, Erasmus University Medical Center–Daniel den Hoed Cancer Center, Rotterdam, The Netherlands</aff><aff id="aff7"><label>7</label>Department of Oncology, Hospital La Paz, Madrid, Spain</aff><aff id="aff8"><label>8</label>Department of Oncology, Peking University School of Oncology, Beijing, China</aff><aff id="aff9"><label>9</label>Department of Dermatology, University of Kiel, Kiel, Germany</aff><aff id="aff10"><label>10</label>Toronto Sunnybrook Regional Cancer Center, Toronto, Canada</aff><aff id="aff11"><label>11</label>The Ella Institute for Treatment and Research of Melanoma, Tel Hashomer, Israel</aff><aff id="aff12"><label>12</label>Immunology and Oncology Unit, Calvary Mater Newcastle Hospital, New South Wales, Australia</aff><author-notes><corresp id="cor1"><label>*</label><italic>Correspondence to:</italic> Dirk Schadendorf, Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany; Tel: +49-201-723-2431; Fax: +49-201-723-5935; E-mail: <email>dirk.schadendorf@uk-essen.de</email></corresp></author-notes><pub-date pub-type="epub-ppub"><month>8</month><year>2009</year></pub-date><pmc-comment>Fake ppub date generated by PMC from publisher pub-date/@pub-type='epub-ppub' </pmc-comment>
<pub-date pub-type="ppub"><month>8</month><year>2009</year></pub-date><pub-date pub-type="pmc-release"><month>8</month><year>2009</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>20</volume><issue>Suppl 6</issue><issue-title>Melanoma: Perspectives of the Global Melanoma Task Force</issue-title><fpage>vi41</fpage><lpage>vi50</lpage><permissions><copyright-statement>© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.</copyright-statement><copyright-year>2009</copyright-year><license license-type="open-access"><license-p>The online version of this article has been published under an open access model. users are entitle to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and the European Society for Medical Oncology are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org</license-p></license></permissions><abstract><p>Immunotherapy of metastatic melanoma consists of various approaches leading to specific or non-specific immunomodulation. The use of FDA-approved interleukin (IL)-2 alone, in combination with interferon α, and/or with various chemotherapeutic agents (biochemotherapy) is associated with significant toxicity and poor efficacy that does not improve overall survival of 96% of patients. Many studies with allogeneic and autologous vaccines have demonstrated no clinical benefit, and some randomised trials even showed a detrimental effect in the vaccine arm. The ongoing effort to develop melanoma vaccines based on dendritic cells and peptides is driven by advances in understanding antigen presentation and processing, and by new techniques of vaccine preparation, stabilisation and delivery. Several agents that have shown promising activity in metastatic melanoma including IL-21 and monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) or CD137 are discussed. Recent advances of intratumour gene transfer technologies and adoptive immunotherapy, which represents a promising although technically challenging direction, are also discussed.</p></abstract><kwd-group><kwd>adoptive immunotherapy</kwd><kwd>anti-CTLA-4</kwd><kwd>interferon</kwd><kwd>interleukin</kwd><kwd>metastatic melanoma</kwd><kwd>vaccine</kwd></kwd-group></article-meta></front><body><sec><title>introduction</title><p>Depending on tumour thickness, mitotic index, presence of ulceration, lymphocyte infiltration, age, gender and anatomical site, 20–25% of all primary melanoma will spread. Dissemination to distant visceral organs is, with the exception of rare cases of surgery for oligometastatic disease, almost invariably a sign of incurable, stage IV disease that has a median survival time of ∼6–12 months and a 3-year survival rate of only 10–15% [<xref ref-type="bibr" rid="bib1">1</xref>]. This is mainly because no treatments of distant metastatic melanoma have demonstrated over the last three decades any survival benefit. Innovative systemic treatment approaches including immunotherapy have focused on metastatic melanoma and are being tested with an increasing intensity. The term ‘immunotherapy’ is used for non-specific as well as specific immunomodulation that encompasses a number of different approaches summarised below.</p></sec><sec><title>cytokines</title><sec><title>interleukin-2 and interferon α</title><p>Interleukin (IL)-2 and interferon (IFN) α are the most widely used immunomodulating drugs in metastatic melanoma. Analysis of eight clinical trials of high-dose IL-2 in 270 patients conducted between 1985 and 1993 [<xref ref-type="bibr" rid="bib2">2</xref>] reported an overall objective response rate of 16% and a complete response in 6% of patients; importantly, ∼4% of patients remained progression-free, which indicates that, in some patients, IL-2 therapy can achieve durable complete remission of the disease. IL-2 (Proleukin) was approved for distant metastatic disease based on a series of phase II studies by the FDA in 1998 in the USA, but not by the EMEA in Europe. Treatment with IL-2 is associated with significant toxicity that includes severe hypotension and vascular leak syndrome, resulting in interstitial and pulmonary oedema, renal and hepatic dysfunction, cardiovascular failure, neurological disturbances, nausea, vomiting and thrombocytopenia [<xref ref-type="bibr" rid="bib3">3</xref>]. This has limited its use to selected patients with good organ function who are treated by experienced clinicians at selected specialised centres.</p><p>Several studies have identified pre-treatment factors predicting response to IL-2 therapy [<xref ref-type="bibr" rid="bib4">4</xref>, <xref ref-type="bibr" rid="bib5">5</xref>]. Univariate analyses revealed that the ECOG performance status, number of involved organs, site of metastases and serum lactate dehydrogenase (LDH) were all predictive of survival in stage IV melanoma. The pre-treatment peripheral neutrophil count was identified as an independent prognostic factor [<xref ref-type="bibr" rid="bib6">6</xref>]; the data were validated on blood samples from patients in the EORTC 18951 biochemotherapy trial [<xref ref-type="bibr" rid="bib7">7</xref>]. These results indicated that selection of patients in stage IV melanoma studies is highly critical; selection of patients for high-dose IL-2 therapy based on performance status, serum LDH and peripheral neutrophil counts seems to be of importance. However, prospective randomised clinical trials are needed to demonstrate whether the patient selection itself or its combination with high-dose IL-2 leads to the observed significant clinical benefit in a subset of patients.</p><p>The most effective IL-2 therapy appears to be the original high-dose bolus regimen used by the National Cancer Institute (NCI) [<xref ref-type="bibr" rid="bib2">2</xref>]. Both long-term, low-dose administration and different subcutaneous schedules have all failed to produce acceptable new regimens with reduced toxicity and higher efficacy compared with that of high-dose IL-2 therapy alone. The continuous infusion schedule has been used in most of the randomised biochemotherapy trials published. A recent report showed a response rate of 19.2% in patients receiving high-dose bolus IL-2 who progressed on biochemotherapy [<xref ref-type="bibr" rid="bib8">8</xref>]. Overall, despite the limited number of patients who benefit from IL-2-based immunotherapy, its curative potential makes it an essential component of immunological strategies in the treatment of metastatic malignant melanoma [<xref ref-type="bibr" rid="bib9">9</xref>].</p><p>IFNα is only rarely used as a single agent in stage IV melanoma, but has achieved objective response rates of ∼10–15 % independent of the dose and schedule [<xref ref-type="bibr" rid="bib10">10</xref>]. Pegylated (PEG) IFNα, an improved IFNα formulation with increased bioavailability [<xref ref-type="bibr" rid="bib11">11</xref>], was recently used in a trial of stage IV metastatic melanoma patients as a single agent and showed dose-dependent response rates in the range 6–12% [<xref ref-type="bibr" rid="bib12">12</xref>]. In recent phase II trials, a combination of PEG-IFNα2a with dacarbazine (DTIC) [<xref ref-type="bibr" rid="bib13">13</xref>] and PEG-IFNα2b with temozolomide [<xref ref-type="bibr" rid="bib14">14</xref>] increased response rates to 24% and 18%, respectively. Combining IFNα and IL-2 did not demonstrate significantly better response rates and survival than those with either agent alone [<xref ref-type="bibr" rid="bib15">15</xref>, <xref ref-type="bibr" rid="bib16">16</xref>].</p><p>Biochemotherapy, a combination of IL-2 and/or IFNα with chemotherapeutic agents such as DTIC, temozolomide, fotemustine, cisplatin, carboplatin, vinblastine, paclitaxel or docetaxel, has also not demonstrated a better survival than that with the agents alone and has been associated with increased toxicity (<xref ref-type="table" rid="tbl1">Table 1</xref>) [<xref ref-type="bibr" rid="bib17">17</xref>, <xref ref-type="bibr" rid="bib18">18</xref>]. In summary, biochemotherapy improves response rates but not OS and cannot be recommended for treatment of metastatic malignant melanoma.</p><table-wrap id="tbl1" position="float"><label>Table 1.</label><caption><p>Randomised trials with IFN- and/or IL-2-containing regimens</p></caption><table frame="hsides" rules="groups"><thead><tr><td rowspan="1" colspan="1">Year (author)</td><td rowspan="1" colspan="1">Regimen</td><td rowspan="1" colspan="1">No. patients</td><td rowspan="1" colspan="1">Median survival (months)</td><td rowspan="1" colspan="1">Signif.</td><td rowspan="1" colspan="1">Ref.</td></tr></thead><tbody><tr><td rowspan="1" colspan="1">1991 (Falkson)</td><td rowspan="1" colspan="1">D ± IFN</td><td align="char" char="." rowspan="1" colspan="1">64</td><td rowspan="1" colspan="1">9.6 versus 17.6</td><td rowspan="1" colspan="1"><italic>P</italic> < 0.01</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib19">19</xref>]</td></tr><tr><td rowspan="1" colspan="1">1993 (Thomson)</td><td rowspan="1" colspan="1">D ± IFN</td><td align="char" char="." rowspan="1" colspan="1">170</td><td rowspan="1" colspan="1">7.6 versus 8.8</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib20">20</xref>]</td></tr><tr><td rowspan="1" colspan="1">1994 (Bajetta)</td><td rowspan="1" colspan="1">D ± IFN<xref ref-type="table-fn" rid="tblfn1">a</xref></td><td align="char" char="." rowspan="1" colspan="1">242</td><td rowspan="1" colspan="1">11 versus 11 versus 13</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib21">21</xref>]</td></tr><tr><td rowspan="1" colspan="1">1998 (Falkson)</td><td rowspan="1" colspan="1">D versus D/IFN versus D/T versus D/IFN/T</td><td align="char" char="." rowspan="1" colspan="1">258</td><td rowspan="1" colspan="1">10 versus 9 versus 8 versus 9.5</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib22">22</xref>]</td></tr><tr><td rowspan="1" colspan="1">2000 (Middleton)</td><td rowspan="1" colspan="1">D/IFN versus DCBT</td><td align="char" char="." rowspan="1" colspan="1">105</td><td rowspan="1" colspan="1">6.5 versus 6.5</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib23">23</xref>]</td></tr><tr><td rowspan="1" colspan="1">2001 (Young)</td><td rowspan="1" colspan="1">D ± IFN</td><td align="char" char="." rowspan="1" colspan="1">61</td><td rowspan="1" colspan="1">7.2 versus 4.8</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib24">24</xref>]</td></tr><tr><td rowspan="1" colspan="1">2005 (Kaufmann)</td><td rowspan="1" colspan="1">TMZ ± IFN</td><td align="char" char="." rowspan="1" colspan="1">282</td><td rowspan="1" colspan="1">8.4 versus 9.7</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib25">25</xref>]</td></tr><tr><td rowspan="1" colspan="1">2005 (Vuoristo)</td><td rowspan="1" colspan="1">D/nIFN versus DCBT/rIFN versus D/rIFN versus DCBT/rIFN</td><td align="char" char="." rowspan="1" colspan="1">108</td><td rowspan="1" colspan="1">11 versus 10 versus 9 versus 7.5</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib26">26</xref>]</td></tr><tr><td rowspan="1" colspan="1">1993 (Sparano)</td><td rowspan="1" colspan="1">IL-2 ± IFN</td><td align="char" char="." rowspan="1" colspan="1">85</td><td rowspan="1" colspan="1">10.2 versus 9.7</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib15">15</xref>]</td></tr><tr><td rowspan="1" colspan="1">2002 (Agarwala)</td><td rowspan="1" colspan="1">IL-2 ± histamine</td><td align="char" char="." rowspan="1" colspan="1">305</td><td rowspan="1" colspan="1">9.1 versus 8.2</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib27">27</xref>]</td></tr><tr><td rowspan="1" colspan="1">1997 (Keilholz)</td><td rowspan="1" colspan="1">IL-2/IFN ± C</td><td align="char" char="." rowspan="1" colspan="1">133</td><td rowspan="1" colspan="1">9 versus 9</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib28">28</xref>]</td></tr><tr><td rowspan="1" colspan="1">1998 (Johnston)</td><td rowspan="1" colspan="1">CDBT ± IFN/IL-2</td><td align="char" char="." rowspan="1" colspan="1">65</td><td rowspan="1" colspan="1">5.5 versus 5.0</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib29">29</xref>]</td></tr><tr><td rowspan="1" colspan="1">1999 (Dorval)</td><td rowspan="1" colspan="1">C/IL-2 ± IFN</td><td align="char" char="." rowspan="1" colspan="1">117</td><td rowspan="1" colspan="1">10.4 versus 10.9</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib30">30</xref>]</td></tr><tr><td rowspan="1" colspan="1">1999 (Rosenberg)</td><td rowspan="1" colspan="1">CDT ± IFN/IL-2</td><td align="char" char="." rowspan="1" colspan="1">102</td><td rowspan="1" colspan="1">15.8 versus 10.7</td><td rowspan="1" colspan="1"><italic>P</italic> < 0.06</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib31">31</xref>]</td></tr><tr><td rowspan="1" colspan="1">2001 (Hauschild)</td><td rowspan="1" colspan="1">D/IFN ± IL-2</td><td align="char" char="." rowspan="1" colspan="1">290</td><td rowspan="1" colspan="1">11 versus 11</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib32">32</xref>]</td></tr><tr><td rowspan="1" colspan="1">2002 (Eton)</td><td rowspan="1" colspan="1">CVD ± IFN/IL-2</td><td align="char" char="." rowspan="1" colspan="1">183</td><td rowspan="1" colspan="1">9.2 versus 11.9</td><td rowspan="1" colspan="1"><italic>P</italic> < 0.06</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib33">33</xref>]</td></tr><tr><td rowspan="1" colspan="1">2002 (Atzpodien)</td><td rowspan="1" colspan="1">D/B/C/T ± IFN/IL-2</td><td align="char" char="." rowspan="1" colspan="1">124</td><td rowspan="1" colspan="1">13 versus 12</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib34">34</xref>]</td></tr><tr><td rowspan="1" colspan="1">2002 (Ridolfi)</td><td rowspan="1" colspan="1">CVD ± IFN/IL-2</td><td align="char" char="." rowspan="1" colspan="1">176</td><td rowspan="1" colspan="1">9.5 versus 11.0</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib35">35</xref>]</td></tr><tr><td rowspan="1" colspan="1">2005 (Keilholz)</td><td rowspan="1" colspan="1">CD/IFN ± IL-2</td><td align="char" char="." rowspan="1" colspan="1">363</td><td rowspan="1" colspan="1">9 versus 9</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib36">36</xref>]</td></tr><tr><td rowspan="1" colspan="1">2006 (Bajetta)</td><td rowspan="1" colspan="1">CVD ± IFN/IL-2</td><td align="char" char="." rowspan="1" colspan="1">139</td><td rowspan="1" colspan="1">12 versus 11</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib37">37</xref>]</td></tr><tr><td rowspan="1" colspan="1">2008 (Atkins)</td><td rowspan="1" colspan="1">CVD ± IFN/IL-2</td><td align="char" char="." rowspan="1" colspan="1">416</td><td rowspan="1" colspan="1">8.7 versus 8.4</td><td rowspan="1" colspan="1">NS</td><td rowspan="1" colspan="1">[<xref ref-type="bibr" rid="bib38">38</xref>]</td></tr></tbody></table><table-wrap-foot><fn id="tblfn1"><label>a</label><p>Dose 3 or 9 MIU.</p></fn><fn><p>D, dacarbazine; C, cisplatin; V, vinblastine; B, BCNU (carmustine); T, tamoxifen; IFN, interferon α; IL-2, interleukin-2; TMZ, temozolomide; NS, not significant; n, natural; r, recombinant.</p></fn></table-wrap-foot></table-wrap></sec><sec><title>interleukins 15 and 21</title><p>The common cytokine receptor γ-chain is a critical component of the receptors for IL-2, 4, 7, 9, 15 and 21. IL-21 and IL-15 have sequence homology with IL-2.</p><p>IL-21 is produced by activated CD4+ T cells and NK-cells. IL-21 has pronounced effects on B cell differentiation and antibody production, mostly via CD40. Furthermore, activation of the IL-21 receptor leads to multiple effects on T cells, including proliferation, differentiation and activation of cytokine and chemokine production. IL-21 has effects on both CD8+ T cells and CD4+ T cells, and synergises with IL-15 in inducing an optimal and sustained antigen-specific CD8+ T cell response [<xref ref-type="bibr" rid="bib39">39</xref>]. In contrast to IL-2, IL-21 does not enhance the proliferation of T regulatory cells. IL-21 may therefore promote autoimmunity and consequently also antitumour immunity in cancer patients.</p><p>IL-15 was initially identified based on its ability to stimulate proliferation of IL-2-dependent T cell lines in the presence of neutralising anti-IL-2 antibodies. IL-15 mediates functions very similarly to IL-2, as these two cytokines share receptor β-subunits. However, distinctly different α-subunits lead to differences in <italic>in vivo</italic> immune function [<xref ref-type="bibr" rid="bib40">40</xref>].</p><p>IL-21 is being investigated in clinical phase I/II studies as a single drug in patients with metastatic melanoma, and recent reports indicate that the treatment is biologically active and well tolerated [<xref ref-type="bibr" rid="bib41">41</xref>, <xref ref-type="bibr" rid="bib42">42</xref>].</p></sec></sec><sec><title>monoclonal antibodies</title><sec><title>anti-cytotoxic T lymphocyte-associated antigen 4</title><p>Activation or ‘priming’ of naïve T cells requires recognition of the antigen by the T cell receptor (TCR) and provision of co-stimulatory signals. The engagement of the molecule B7 on the antigen-presenting cell with its ligand CD28 on the T cell launches a signalling cascade that is required for full T cell activation [<xref ref-type="bibr" rid="bib43">43</xref>]. Following antigen stimulation of the T cell, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) receptors are up-regulated and move to the cell surface. These receptors have greater affinity for B7 than CD28, and their binding induces an inhibitory signal that down-regulates T cell activation in response to a stimulus. CTLA-4 serves as a natural breaking mechanism that returns T cells to homeostasis following an immune response; it controls the duration and intensity of the immune response.</p><p>Monoclonal antibodies that bind to CTLA-4 can block the interaction between B7 and CTLA-4. Inhibition of this negative switch may break peripheral tolerance to self-tissues and induce antitumour responses [<xref ref-type="bibr" rid="bib44">44</xref>]. Two fully human IgG monoclonal antibodies recognising CTLA-4, ipilimumab (MDX-010) and tremelimumab (CP-675,206), have been tested, alone or in combination, in numerous phase II trials and in four phase III trials. Comprehensive reviews were recently published on targeting the CTLA-4 receptor as a strategy for melanoma treatment [<xref ref-type="bibr" rid="bib45">45</xref>, <xref ref-type="bibr" rid="bib46">46</xref>], and on clinical development of ipilimumab [<xref ref-type="bibr" rid="bib47">47</xref>] and tremelimumab [<xref ref-type="bibr" rid="bib48">48</xref>].</p></sec><sec><title>ipilimumab</title><p>Activity of ipilimumab in patients with metastatic melanoma was examined alone, in combination with chemotherapy or vaccines and in various dose regimens.</p><p>In a randomised phase II trial, 72 chemotherapy-naïve patients were treated with ipilimumab (3 mg/kg every 4 weeks for 4 months) alone or in combination with DTIC. The median OS for the monotherapy and combination groups was 351 [95% CI, 208–596] and 386 [95% CI, 253–571] days, respectively, and ∼10% of patients were alive after 2 to >4 years of follow-up in both therapy arms, indicating that the treatment can achieve long-term control of the disease [<xref ref-type="bibr" rid="bib49">49</xref>].</p><p>To assess the activity of ipilimumab in combination with a vaccine, 56 patients were randomised in a phase II study of 3 mg/kg every 3 weeks or a 3 mg/kg initial dose of ipilimumab followed by 1 mg/kg every 3 weeks, with both cohorts receiving concomitant vaccination with two modified HLA-A*0201-restricted peptides [<xref ref-type="bibr" rid="bib50">50</xref>]. Overall response rate was 13%; better clinical responses were observed in patients with grade 3/4 autoimmune toxicity. This result was later confirmed by a subsequent analysis of additional data, which reported that some of the immune-related adverse events were observed in 62% of 139 overall treated patients and were associated with a greater probability of objective antitumour response (<italic>P</italic> = 0.0004) [<xref ref-type="bibr" rid="bib51">51</xref>]. The most common grade 3/4 immune-related adverse events were colitis/diarrhoea and dermatitis, which responded to systemic steroids without significantly affecting the efficacy of ipilimumab therapy [<xref ref-type="bibr" rid="bib52">52</xref>]. These studies indicate that induction of manageable autoimmunity in patients with metastatic melanoma treated with ipilimumab could be a surrogate marker of objective and durable clinical response.</p><p>Although earlier studies used ipilimumab at doses of 3 mg/kg every 3–4 weeks, results from more recent dose-escalation trials showed an increase in overall response and long-term survival benefits with increasing dose, and suggested 10 mg/kg every 3 weeks for 4 months (Q3Wx4) as an optimal treatment [<xref ref-type="bibr" rid="bib53">53</xref>]. This induction regimen along with a maintenance treatment of 10 mg/kg ipilimumab every 12 weeks starting at week 24 (Q12W) has been used in most ongoing phase II and phase III clinical trials.</p><p>The Q3Wx4 regimen of ipilimumab with Q12W maintenance showed clinical activity in the form of either objective response or stable disease in 27% of 155 patients with metastatic melanoma who developed progressive disease on a median number of two prior therapies [<xref ref-type="bibr" rid="bib54">54</xref>]. Immune-related grade 3/4 adverse events occurred in 21.9% of patients. The study reported median OS of 10.2 months and 1-year survival of 46.7% (95% CI, 38.6–55.6). Four patterns of response were observed: (a) response in baseline lesions; (b) stable disease with slow, steady decline in total tumour burden; (c) response after initial increase in total tumour burden; (d) response in index and new lesions after the appearance of new lesions [<xref ref-type="bibr" rid="bib54">54</xref>]. It is of note that 7 of 26 patients who developed new lesions after 12 weeks of treatment experienced shrinking and stabilisation of the new lesions during additional follow-up. This result demonstrated that development of new lesions in patients receiving ipilimumab might not always indicate progressive disease and treatment failure as defined by modified World Health Organization (mWHO) criteria [<xref ref-type="bibr" rid="bib55">55</xref>]. Novel, immune-related response criteria (irRC) that may more accurately describe response to immunotherapy and avoid premature treatment cessation in patients with disease progression before response were presented at ASCO 2008. Contrary to mWHO criteria, irRC (a) only consider measurable lesions (>1 cm), (b) define total tumour burden as the sum of index lesions identified at baseline and new lesions detected after baseline and (c) aim for follow-up after progressive disease to detect late activity [<xref ref-type="bibr" rid="bib56">56</xref>].</p><p>Overall positive results of ipilimumab in patients with metastatic melanoma led to the initiation of a pivotal trial in first-line treatment comparing DTIC with or without ipilimumab. Another phase III trial of ipilimumab alone or in combination with a peptide vaccine as second-line therapy is also ongoing.</p></sec><sec><title>tremelimumab</title><p>Early-phase clinical studies of tremelimumab demonstrated acceptable toxicity (diarrhoea/colitis, dermatitis, fatigue, pancreatitis, Grave's disease) and similar efficacy of 10 mg/kg monthly and 15 mg/kg quarterly doses of the antibody [<xref ref-type="bibr" rid="bib57">57</xref>] with median survival of 10.3 and 11 months, respectively [<xref ref-type="bibr" rid="bib58">58</xref>]. Survival outcomes were better than the historical median survival of 7 months and independent of the patients’ objective response [<xref ref-type="bibr" rid="bib58">58</xref>].</p><p>Activity of tremelimumab as a single agent (15 mg/kg quarterly, ≥1 dose, 44% of patients ≥2 doses) in 246 previously treated patients with metastatic melanoma was assessed in a single-arm phase II study. Although the objective response rate was only 8.3%, the duration of the response (183+ to 540+ days) and the median OS of 10.1 months indicate a role for tremelimumab in this patient population [<xref ref-type="bibr" rid="bib59">59</xref>].</p><p>The quarterly dose regimen (15 mg/kg) was chosen for a phase III clinical trial since it was associated with a lower incidence of serious adverse events and comparable efficacy [<xref ref-type="bibr" rid="bib57">57</xref>]. That trial, a randomised study investigating tremelimumab as a single agent in comparison with a standard chemotherapy (DTIC or temozolomide) in previously untreated 324 and 319 patients, respectively, was stopped based on a second interim analysis for futility in March 2008. Median OS by intent-to-treat was 11.8 months in the tremelimumab arm, and 10.7 months in the chemotherapy arm, with a hazard ratio (HR) (chemotherapy over tremelimumab) of 1.04 (95% CI, 0.84, 1.28). The study concluded that the antibody failed to demonstrate an improvement in OS as a first-line treatment in patients with metastatic melanoma when compared with standard chemotherapy [<xref ref-type="bibr" rid="bib60">60</xref>]. Data from subsequent phase II and phase III studies will be useful to further evaluate the dosing regimen and the relationship between tumour response and survival.</p><p>A combination of tremelimumab (15 mg/kg quarterly) administered concurrently with high-dose IFNα2b was assessed in a phase II trial of 16 previously treated patients with metastatic melanoma and showed acceptable toxicity and an overall response rate of 19% [<xref ref-type="bibr" rid="bib61">61</xref>].</p><p>Collectively, development of therapies based on selective inhibition of the CTLA-4 receptor with monoclonal antibodies is a promising direction in treatment of stage IV melanoma, but the recently reported lack of efficacy of tremelimumab as a single agent in first-line treatment indicates that future investigative efforts of anti-CTLA-4 agents may focus on combination studies and patients with refractory tumours. Also, the unique kinetics of response to ipilimumab therapy will likely lead to revision of the criteria that describe response to CTLA-4 antibodies.</p></sec><sec><title>anti-CD137 (4-1BB)</title><p>Inducible receptor-like protein 4-1BB is expressed by both CD4+ and CD8+ T cells after activation. Cross-linking of 4-1BB, either by 4-1BB ligand binding or antibody ligation, delivers a co-stimulatory signal to enhance T cell activation and proliferation. Pre-clinical studies demonstrated that the administration of 4-1BB (CD137) monoclonal antibodies can induce antitumour immune responses. In a pre-clinical B-16 mouse melanoma model, a combination of granulocyte monocyte colony-stimulating factor (GM-CSF)-secreting tumour cell immunotherapy and anti-4-1BB monoclonal antibody treatment resulted in rejection of established tumours [<xref ref-type="bibr" rid="bib62">62</xref>]. In a pre-clinical B16F10 mouse melanoma model, a combination treatment with anti-CD4+ and anti 4-1BB monoclonal antibodies potentiated the observed anti-cancer effects [<xref ref-type="bibr" rid="bib63">63</xref>]. A phase I dose-escalation study of BMS-663513, an agonist anti-CD137 human monoclonal antibody, in 54 metastatic melanoma patients reported manageable toxicity (up to 15 mg/kg), with fatigue, transaminitis and neutropenia being the most common adverse events, and clinical activity that justifies its further development both as a single agent and in combination [<xref ref-type="bibr" rid="bib64">64</xref>]. A large, randomised phase II clinical study with BMS-663513 in previously treated melanoma patients with stage IV disease is currently ongoing.</p></sec><sec><title>anti-integrin</title><p>Human monoclonal antibody targeting α<sub>v</sub> integrin, CNTO 95, was found to inhibit growth of human melanoma tumours in nude mice (10 mg/kg, 3 times a week) by ∼80% and in nude rats by >99% [<xref ref-type="bibr" rid="bib65">65</xref>]. Based on these preclinical data, a dose-escalating phase I clinical trial assessed the safety and pharmacokinetics of CNTO 95 in 24 patients with advanced refractory solid tumours. The antibody was well tolerated up to weekly doses of 10 mg/kg, and had a dose-dependent half-life ranging from 0.19 to 11.81 days over the doses 0.1–10 mg/kg, indicating tissue binding at low doses [<xref ref-type="bibr" rid="bib66">66</xref>]. An ongoing phase I/II trial is investigating the safety and efficacy of CNTO 95 alone or in combination with DTIC in 138 patients with metastatic melanoma.</p><p>Volociximab (M200) is a chimeric monoclonal antibody that specifically recognises α5β1 integrin and inhibits tumour angiogenesis by interrupting the binding of endothelial cells to fibronectin in extracellular matrix. A pilot, single-arm phase II study of 40 patients with metastatic melanoma tested a combination of volociximab (10 mg/kg i.v. bi-weekly) with DTIC (1000 mg/m<sup>2</sup> monthly) and reported stable disease in 53% of patients at 8 weeks with median time to progression 72 days. The combination therapy was relatively well tolerated, with reported adverse events including nausea, constipation, vomiting, hypertension and thrombosis [<xref ref-type="bibr" rid="bib67">67</xref>]. A recent phase II study of volociximab (15 mg/kg weekly for 8 weeks) as a single agent in 19 patients who failed at least one prior therapy reported poor clinical activity at 8 weeks (overall response rate of 5%) but indicated a potential correlation between the expression of α5β1 integrin in tumours or stroma and clinical response [<xref ref-type="bibr" rid="bib68">68</xref>].</p><p>Etaracizumab (Abegrin), formerly known as Vitaxin or MEDI-522, is a humanised monoclonal antibody that specifically targets the integrin αvβ3 overexpressed on various tumour cells, angiogenic blood vessels and osteoclasts, and results in antitumour, antiangiogenic and antiosteolytic activities [<xref ref-type="bibr" rid="bib69">69</xref>]. Results from a phase II study in 112 patients with distant metastatic melanoma examined antitumour activity and safety of etaracizumab (8 mg/kg/week) with or without DTIC (1000 mg/m<sup>2</sup> once every 3 weeks). The therapy with or without DTIC reported median progression-free survival of 2.6 or 1.4 months, respectively, and was generally well tolerated with adverse events including neutropenia, thrombocytopenia, anaemia and leukopenia. Approximately 70% of patients were alive at 6 months in each arm [<xref ref-type="bibr" rid="bib70">70</xref>]. Later evaluation of the trial data showed a 12.7-month median survival for patients treated with etaracizumab alone and a 9.4-month median survival for patients treated with etaracizumab plus DTIC, indicating that the antibody may prolong survival in melanoma patients. However, a 24-month follow-up was less positive and resulted in withdrawal of the agent from further development in metastatic melanoma at the end of 2006.</p></sec></sec><sec><title>vaccines</title><p>The rationale for developing a melanoma therapeutic vaccine is based on several observations: (a) the ability of melanoma to initiate an immune response that can induce spontaneous regression; (b) the effectiveness of vaccines for treating melanoma in animal models; (c) the association of the presence of lymphocytic tumour infiltration with prognosis in melanoma patients; (d) the identification of numerous human melanoma-associated antigens; (e) relatively low toxicity and few side-effects of vaccines in humans with melanoma.</p><p>Rosenberg and co-workers [<xref ref-type="bibr" rid="bib71">71</xref>] stated that despite great progress in the field of tumour immunology over the past decade, optimism regarding the clinical application of currently available cancer vaccine approaches is based more on surrogate end points than on clinical tumour regression. In the NCI surgery branch cancer vaccine trials involving 440 metastatic cancer patients (96% melanoma), the objective response rate was very low (2.6%) and was comparable to the response rate of 4.0% obtained by others in 40 studies including 756 patients [<xref ref-type="bibr" rid="bib71">71</xref>]. These disappointing results in patients with distant metastatic melanoma are often softened by arguments that such immunosuppressed patients are unsuitable for vaccine development studies and that vaccines will likely be successful only in immune-competent patients after full resection of their tumour(s) (adjuvant setting). However, it is precisely in this setting (large adjuvant trials in resected stage II–IV melanoma) where results with vaccines have not been positive or even indicated that the vaccines are potentially detrimental.</p><sec><title>allogeneic and autologous vaccines</title><p>The vaccination of tumour patients with autologous and allogeneic cell-based vaccines has a long tradition [<xref ref-type="bibr" rid="bib72">72</xref>]. The largest two studies to date, which assessed the efficacy of an allogeneic cancer vaccine from three cell lines (Canvaxin) in patients with stage III or IV melanoma, were closed prematurely based on the advice of the Independent Data Monitoring Committee (IDMC) [<xref ref-type="bibr" rid="bib73">73</xref>]. In these trials, >1400 patients were randomised to Canvaxin + bacillus Calmette–Guerin (BCG) or placebo + BCG after resectional surgery. There was a survival disadvantage with Canvaxin treatment in both studies. The median survival in the stage III study had not been reached, but the 5-year survival rate was 59% for the Canvaxin patients and 68% for the placebo patients. In the stage IV study, the median survival was 32 months for the Canvaxin patients and 39 months for the placebo patients, with a 5-year survival of 40% and 45%, respectively.</p><p>In contrast to allogeneic vaccines, autologous vaccines are prepared from tumours of individual patients. Vitespen (Oncophage, formerly HSPPC-96) is a tumour-derived, HSP–peptide complex vaccine based on the pioneering work of Pramod K. Srivastava [<xref ref-type="bibr" rid="bib74">74</xref>]. It was earlier examined in a trial with 64 stage IV melanoma patients [<xref ref-type="bibr" rid="bib75">75</xref>] and showed no toxicity of the treatment and increased T cell activity associated with the vaccine application.</p><p>The most recent, phase III trial comparing Vitespen with a physician choice therapy (2:1 randomisation) in 322 stage IV cutaneous melanoma patients not previously treated for metastatic disease found similar overall survival (OS) in both arms (<italic>P</italic> = 0.32; HR = 1.16; 95% CI, 0.69–1.71) based on intention-to-treat analysis of survival for all patients [<xref ref-type="bibr" rid="bib76">76</xref>]. Non-significant difference was also found for OS of patients stratified by substage (M1a, M1b, M1c). However, exploratory landmark analysis of survival of patients who received >10 vaccines showed, after adjustment for survival bias, a separation of both arms in Kaplan–Meier plots in favour of the Vitespen-treated patients for all patients and statistical significance for combined data from M1a + M1b patients (<italic>P</italic> = 0.03; HR = 0.45; 95% CI, 0.21–0.96). The study also reported a correlation between the number of immunisations and improved survival in favour of the vaccine in all patients, as well as in M1a and M1b, but not M1c, substages [<xref ref-type="bibr" rid="bib76">76</xref>]. Whether these results will be convincing enough for further clinical development is still open.</p></sec><sec><title>MAGE-3</title><p>A number of clinical trials involving antigens encoded by genes of the MAGE family, particularly MAGE-3, have been documented and demonstrated tumour regression in melanoma patients [<xref ref-type="bibr" rid="bib77">77</xref>]. These tumour regressions appeared to be mediated by low-level cytolytic T lymphocyte (CTL) responses. A recombinant MAGE-A3 fusion protein—Prot.D MAGE-A3/His—was engineered as a fusion protein with a lipidated protein D derived from <italic>Haemophilus influenzae</italic>. A recent, proof-of-concept, randomised, open study with the MAGE-A3 protein combined with different immunological adjuvants—AS02B or AS15—assessed the adjuvants for toxicity and clinical and immunological responses. The MAGE-A3 protein was administered as first-line treatment to 68 patients with unresectable stage III or stage IV M1a melanoma; in combination with AS15 it yielded higher anti-MAGE-3 antibody titre, stronger T cell induction and long-lasting clinical response [<xref ref-type="bibr" rid="bib78">78</xref>]. A randomised trial in patients with resected stage IIIB and IIIC melanoma is planned to commence in late 2008.</p></sec><sec><title>peptide-based vaccines</title><p>The identification of tumour-specific antigens recognised by autologous cytolytic CD8+ T cells has led to the use of defined antigens in therapeutic vaccination of cancer patients. Although overall response rates to all peptide-based vaccines have been disappointing in distant metastatic melanoma patients [<xref ref-type="bibr" rid="bib71">71</xref>], a new interest is stimulated by insights into tissue-specific processing of the immunogenic epitopes of proteins and by the discovery of unusually long cytotoxic T lymphocyte epitopes that may lead to identification of new targets and an improvement in peptide immunogenicity [<xref ref-type="bibr" rid="bib79">79</xref>]. Longer peptides harbouring particular peptide epitopes allow adequate epitope processing and consequently better peptide vaccine efficacy [<xref ref-type="bibr" rid="bib80">80</xref>]; also, they can be synthesised with known post-translational modifications and/or protease-resistant peptide bonds to regulate their processing independently of tissue-specific proteolysis, and to stabilise them <italic>in vivo</italic> [<xref ref-type="bibr" rid="bib79">79</xref>].</p></sec><sec><title>dendritic-cell-based vaccines</title><p>Dendritic cells (DCs) play a crucial role in the induction of antigen-specific T cell responses and are considered to be promising adjuvants for use in active immunotherapy of metastatic malignancies. The generation of immune responses against tumour antigens following DC immunisation has been demonstrated, and favourable clinical responses have been reported in some patients [<xref ref-type="bibr" rid="bib81">81</xref>]. However, the data on the usefulness of DCs for melanoma immunotherapy remain inconclusive because of varying DC preparation and vaccination protocols, the use of different antigens and a lack of rigorous criteria for defining clinical responses. Issues regarding the optimal dose and clinical setting for the application of DC vaccines remain to be resolved.</p><p>In one of the earliest studies [<xref ref-type="bibr" rid="bib82">82</xref>], DCs pulsed with MAGE-3A1 tumour peptide and a recall antigen (tetanus toxoid or tuberculin) were injected into 11 advanced stage IV melanoma patients. A significant expansion of MAGE-3A1-specific CD8+ cytotoxic T lymphocyte precursors were induced in eight of those patients, and regressions of individual skin metastases were observed in six patients. Regressing skin metastases in two of the patients demonstrated erythema and CD8+ T cell infiltration, whereas non-regressing lesions lacked CD8+ T cells as well as MAGE-3 mRNA expression.</p><p>In a randomised phase III trial conducted by Schadendorf et al. [<xref ref-type="bibr" rid="bib83">83</xref>], patients received autologous peptide-loaded DC vaccination or DTIC (850 mg/m<sup>2</sup>) at 4-week intervals. DC vaccines loaded with MHC class I and II-restricted peptides were applied subcutaneously at 2-week intervals for the first five vaccinations and every 4 weeks thereafter. At the time of the first interim analysis, 55 and 53 patients had been enrolled into the DTIC- and DC-arm, respectively. Since the overall response was low (DTIC: 5.5%, DC: 3.8%) and not significantly different in the two arms, the study was closed. Many factors could have affected the efficacy of the vaccine. These include the low and variable maturation status of DCs, administration of lower than the expected number of DCs per class I peptide, subcutaneous instead of intradermal route of administration and a lack of non-specific helper proteins like KLH or tetanus toxoid. Although various small clinical phase I/II studies were conducted using DCs, no results of other randomised trials in melanoma have been published [<xref ref-type="bibr" rid="bib84">84</xref>]. Current technologies try to benefit from improved understanding of DC biology and use mostly transfection techniques of RNA from the whole tumour or RNA of specific tumour antigens.</p><p>In summary, vaccine development in melanoma has gone through a difficult phase and, to date, no vaccination procedure has shown statistically significant efficacy in the adjuvant or metastatic setting [<xref ref-type="bibr" rid="bib85">85</xref>]. Currently available data do not justify the use of vaccination for the treatment of patients with cutaneous melanoma outside of a clinical trial.</p></sec></sec><sec><title>intratumoural gene transfer therapy</title><p>The first clinical trial of gene therapy for cancer was performed in the early 1990s in patients with melanoma, and several intratumoural gene-therapy-based protocols have been attempted since then. Conclusive evidence demonstrating the clinical efficacy and therapeutic response using this approach for melanoma is yet to be established.</p><p>A phase I/II study [<xref ref-type="bibr" rid="bib86">86</xref>] was recently conducted to evaluate the safety, efficacy and biological effects of intratumoural injections of adenovirus–IL-2 (TG1024) in patients with advanced solid tumours including melanoma. Twenty-five patients with metastatic melanoma were treated with intratumoural TG1024 injections in combination with DTIC. Objective responses were observed in five metastatic melanoma patients, of whom two demonstrated complete responses [<xref ref-type="bibr" rid="bib86">86</xref>].</p><p>Intratumoural injections of a plasmid harbouring the IL-12 gene in nine stage IV melanoma patients [<xref ref-type="bibr" rid="bib87">87</xref>] resulted in clinical benefit in three patients, and eight patients exhibited transient responses. Successful results were also observed when intratumoural injections of a similar plasmid were used to treat lesions in 12 metastatic melanoma patients in a phase I/IB trial [<xref ref-type="bibr" rid="bib88">88</xref>]. The size of the treated lesions decreased by >30% in 5 of the 12 patients. No responses were seen in untreated lesions.</p><p>Results from a recent phase II study with intratumour injections (up to 18 cycles) of OncoVEX<sup>GM-CSF</sup>—an oncolytic herpes simplex virus vector encoding GM-CSF—into 43 stage IIIc and IV patients who failed previous therapies reported an encouraging 28% objective response and very minor side-effects [<xref ref-type="bibr" rid="bib89">89</xref>]. Injected tumours routinely responded, often with local complete response, within 2 months of therapy. More importantly, systemic long-term responses were observed. The responses were observed late and were independent of the disease stage: six complete responses, six partial responses and seven stable diseases were reported. A phase III trial in 360 previously treated, unresectable melanoma patients is planned and will be initiated at the beginning of 2009.</p><p>These results show that intratumoural injections of a cytokine gene can produce beneficial clinical effects and that intratumoural gene therapy may be a promising therapy for patients with metastatic melanoma.</p></sec><sec><title>adoptive immunotherapy</title><p>Adoptive cell transfer (ACT) immunotherapy is based on <italic>ex vivo</italic> activation and expansion of tumour reactive lymphocytes taken from the tumour-bearing host and their re-infusion back into the patient [<xref ref-type="bibr" rid="bib90">90</xref>].</p><p>The availability of the T cell growth factor in the form of recombinant IL-2 in the 1980s promoted the investigation and use of cell therapy in human cancer with lymphokine activated killer (LAK) cells and IL-2, demonstrating non-specific antitumour activity [<xref ref-type="bibr" rid="bib91">91</xref>]. On the other hand, tumour-infiltrating lymphocytes (TILs) are T cells that have specific antitumour activity, and in melanoma these cells can be reliably generated [<xref ref-type="bibr" rid="bib92">92</xref>].</p><p>Eighty-six patients with metastatic melanoma were treated with TILs and high-dose (HD) IL-2 in the early 1990s. The overall response rate was 34%, and responses were also documented in patients failing prior HD IL-2 therapy [<xref ref-type="bibr" rid="bib93">93</xref>]. In 2002 Dudley et al. [<xref ref-type="bibr" rid="bib94">94</xref>] reported that ACT of highly selected tumour-reactive T cells into 13 HLA-A2<sup>+</sup> refractory metastatic melanoma patients after a non-myeloablative conditioning regimen approach resulted in the persistent clonal repopulation of T cells in these cancer patients, proliferation of transferred cells <italic>in vivo</italic>, functional activity of T cells and trafficking to tumour sites. Six of the 13 patients had objective clinical responses to treatment, and four patients demonstrated mixed responses. This study established the proof of principle that normally expressed ‘self-antigens’ can be useful targets for human tumour immunotherapy if the autoimmune consequences of such treatment are not of major concern.</p><p>Mackensen et al. [<xref ref-type="bibr" rid="bib95">95</xref>] generated Melan-A-specific CTLs by <italic>ex vivo</italic> stimulation of purified CD8+ peripheral blood lymphocytes with mature Melan-A pulsed DCs and reported that 3 of 11 patients experienced objective clinical responses after infusion of the T cells with a 6-day course of low-dose IL-2. Regression of melanoma lesions was observed in subcutaneous and lymphatic, but not in visceral metastases. Powell et al. [<xref ref-type="bibr" rid="bib96">96</xref>] treated nine patients with distant metastatic melanoma who were vaccinated with GP-100:209–217 peptide. The patients received autologous peripheral blood mononuclear cells stimulated <italic>ex vivo</italic> with the peptide and were pretreated with non-myeloablative chemotherapy; the cells were given concomitantly with high-dose IL-2. Two patients experienced some evidence of melanocyte-directed autoimmunity [<xref ref-type="bibr" rid="bib96">96</xref>].</p><p>A recent report [<xref ref-type="bibr" rid="bib97">97</xref>] demonstrated a durable clinical remission of a patient with refractory metastatic melanoma who was treated with autologous CD4 T cell clones specific for melanoma-associated antigen NY-ESO-1, isolated and expanded <italic>ex vivo</italic>; the treatment also led to endogenous responses against melanoma antigens other than NY-ESO-1 [<xref ref-type="bibr" rid="bib97">97</xref>].</p><p>Studies carried out at the surgery branch of NCI demonstrated that, in addition to IL-2, lymphodepletion with chemotherapy was crucial to support the transferred cells. Lymphodepletion was believed to eliminate T regulatory (suppressor) cells and to reduce competition for homeostatic cytokines (IL-7, IL-15) vital for T cell survival. Bulk TIL populations that were rapidly expanded <italic>in vitro</italic> were preferred over cloned TIL populations [<xref ref-type="bibr" rid="bib98">98</xref>]. The protocol used a non-myeloablative but lymphodepleting regimen consisting of i.v. administration of cyclophosphamide (60 mg/kg/day for 2 days) followed by fludarabine (25 mg/m<sup>2</sup>/day for 5 days). This was followed by the administration of bulk TILs and HD IL-2. A response rate of 51% was achieved in the first 35 metastatic melanoma patients, with three patients achieving a durable complete response ongoing for >3 years after therapy. Further improvement in the clinical efficacy of the TIL programme was achieved by adding total body irradiation with up to 1200 cGy in three divided doses. The patients treated with this programme received peripheral stem cell support, and the response rate reached 70% [<xref ref-type="bibr" rid="bib99">99</xref>].</p><p>Conversion of normal peripheral blood lymphocytes (PBLs) into antitumour cells by transduction with genes encoding one of the TCRs relevant to tumour cells is under study [<xref ref-type="bibr" rid="bib100">100</xref>]. This approach is being explored for the immunotherapy of patients with melanoma and common epithelial cancers. Thirty-one patients with metastatic melanoma were treated by autologous PBLs transduced by MART-1-specific TCRs following non-myeloablative conditioning. Four patients had objective tumour regression [<xref ref-type="bibr" rid="bib99">99</xref>].</p><p>Studies to optimise ACT include examination of the role of cytokines such as IL-7, IL-15 and others, and the addition of other immunomodulatory agents such as anti-CTLA-4. One of the most important steps toward developing a technically more simple way of producing effective TILs is by using ‘young’, unselected TILs. This technology uses the entire tumour to rapidly expand TILs for administration without testing for antitumour reactivity. This simple method may facilitate the adoption of ACT by more cancer centres and provide this effective therapy to more patients [<xref ref-type="bibr" rid="bib101">101</xref>].</p></sec><sec sec-type="conclusion"><title>conclusion</title><p>The poor efficacy and high toxicity of current immunotherapeutic approaches used to treat distant metastatic melanoma underscore an urgent need for novel therapies that take advantage of recent advances in understanding the biology of the disease. In parallel, introducing novel criteria for the selection of potential therapy responders would result in a more targeted use of current therapies and spare future non-responders from unnecessary toxicity.</p><p>Early clinical trials with monoclonal antibodies targeting CTLA-4, CD137 or integrins show generally manageable toxicity, and results from large randomised studies are needed to assess the future role of these agents in metastatic melanoma. Combinations with cytotoxic agents appears to be the likely direction, mainly in patients with refractory tumours. Development of a vaccine that would show significant clinical benefit in melanoma has not been successful, but the extent of research activity in the field and a number of novel approaches indicate that such an approach remains attractive. Intratumoural gene transfer represents a promising direction of yet uncertain clinical benefit. Adoptive therapy has demonstrated a remarkable response rate and efficacy in a number of small studies, but it is a complex and labour-intensive technology that would require extensive optimisation before its introduction into mainstream clinical practice.</p></sec><sec><title>conflict of interest disclosures</title><p>S. M. Algarra has had an advisory role with Pfizer and has received honoraria from Schering-Plough; L. Bastholt has had an advisory role with Schering Plough, Celgene, Pfizer, Genmab and AstraZeneca, and has received honoraria for educational lectures from Schering-Plough and AstraZeneca; G. Cinat has served as advisor for Pfizer and received lecture honoraria from Pfizer; B. Dreno has been a member of a French national board supported by Schering Plough; A. M. M. Eggermont has been consultant for Schering-Plough and Bristol-Myers Squibb; E. Espinosa has received honoraria from Schering-Plough; A. Hauschild has received consultancy and speaker's honoraria from Schering-Plough/Essex Pharma (USA/Germany), and has been a member of consultancy/advisory boards for Pfizer and Bristol-Myers Squibb (USA) and a member of an advisory board for GlaxoSmithKline (USA/Europe); T. Petrella has had an advisory role with Pfizer, Novartis (Chiron) and Schering-Plough; J. Schachter has received research funding from Schering-Plough and Pfizer; D. Schadendorf has had an advisory role for Bristol-Myers Squibb, AstraZeneca, GlaxoSmithKline, Schering-Plough, Synta Pharmaceuticals, Bayer and Altona, and has received research support from Schering-Plough.</p></sec></body><back><ack><p>The authors thank Pavel Kramata, ScienceFirst, LLC, Cedar Knolls, NJ 07927, USA for writing support and coordination during preparation of the manuscript.</p></ack><ref-list><ref id="bib1"><label>1.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Balch</surname><given-names>CM</given-names></name><name><surname>Buzaid</surname><given-names>AC</given-names></name><name><surname>Soong</surname><given-names>SJ</given-names></name><etal></etal></person-group><article-title>Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma</article-title><source>J Clin Oncol</source><year>2001</year><volume>19</volume><fpage>3635</fpage><lpage>3648</lpage><pub-id pub-id-type="pmid">11504745</pub-id></element-citation></ref><ref id="bib2"><label>2.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Atkins</surname><given-names>MB</given-names></name><name><surname>Lotze</surname><given-names>MT</given-names></name><name><surname>Dutcher</surname><given-names>JP</given-names></name><etal></etal></person-group><article-title>High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993</article-title><source>J Clin Oncol</source><year>1999</year><volume>17</volume><fpage>2105</fpage><lpage>2116</lpage><pub-id pub-id-type="pmid">10561265</pub-id></element-citation></ref><ref id="bib3"><label>3.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tsao</surname><given-names>H</given-names></name><name><surname>Atkins</surname><given-names>MB</given-names></name><name><surname>Sober</surname><given-names>AJ</given-names></name></person-group><article-title>Management of cutaneous melanoma</article-title><source>N Engl J Med</source><year>2004</year><volume>351</volume><fpage>998</fpage><lpage>1012</lpage><pub-id pub-id-type="pmid">15342808</pub-id></element-citation></ref><ref id="bib4"><label>4.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Keilholz</surname><given-names>U</given-names></name><name><surname>Conradt</surname><given-names>C</given-names></name><name><surname>Legha</surname><given-names>SS</given-names></name><etal></etal></person-group><article-title>Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients</article-title><source>J Clin Oncol</source><year>1998</year><volume>16</volume><fpage>2921</fpage><lpage>2929</lpage><pub-id pub-id-type="pmid">9738559</pub-id></element-citation></ref><ref id="bib5"><label>5.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Phan</surname><given-names>GQ</given-names></name><name><surname>Attia</surname><given-names>P</given-names></name><name><surname>Steinberg</surname><given-names>SM</given-names></name><etal></etal></person-group><article-title>Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma</article-title><source>J Clin Oncol</source><year>2001</year><volume>19</volume><fpage>3477</fpage><lpage>3482</lpage><pub-id pub-id-type="pmid">11481353</pub-id></element-citation></ref><ref id="bib6"><label>6.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schmidt</surname><given-names>H</given-names></name><name><surname>Bastholt</surname><given-names>L</given-names></name><name><surname>Geertsen</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model</article-title><source>Br J Cancer</source><year>2005</year><volume>93</volume><fpage>273</fpage><lpage>278</lpage><pub-id pub-id-type="pmid">16052222</pub-id></element-citation></ref><ref id="bib7"><label>7.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schmidt</surname><given-names>H</given-names></name><name><surname>Suciu</surname><given-names>S</given-names></name><name><surname>Punt</surname><given-names>CJ</given-names></name><etal></etal></person-group><article-title>Pretreatment levels of peripheral neutrophils and leukocytes as independent predictors of overall survival in patients with American Joint Committee on Cancer Stage IV Melanoma: results of the EORTC 18951 biochemotherapy trial</article-title><source>J Clin Oncol</source><year>2007</year><volume>25</volume><fpage>1562</fpage><lpage>1569</lpage><pub-id pub-id-type="pmid">17443000</pub-id></element-citation></ref><ref id="bib8"><label>8.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tarhini</surname><given-names>AA</given-names></name><name><surname>Kirkwood</surname><given-names>JM</given-names></name><name><surname>Gooding</surname><given-names>WE</given-names></name><etal></etal></person-group><article-title>Durable complete responses with high-dose bolus interleukin-2 in patients with metastatic melanoma who have experienced progression after biochemotherapy</article-title><source>J Clin Oncol</source><year>2007</year><volume>25</volume><fpage>3802</fpage><lpage>3807</lpage><pub-id pub-id-type="pmid">17761969</pub-id></element-citation></ref><ref id="bib9"><label>9.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Petrella</surname><given-names>T</given-names></name><name><surname>Quirt</surname><given-names>I</given-names></name><name><surname>Verma</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Single-agent interleukin-2 in the treatment of metastatic melanoma: a systematic review</article-title><source>Cancer Treat Rev</source><year>2007</year><volume>33</volume><fpage>484</fpage><lpage>496</lpage><pub-id pub-id-type="pmid">17562357</pub-id></element-citation></ref><ref id="bib10"><label>10.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Legha</surname><given-names>SS</given-names></name></person-group><article-title>The role of interferon alfa in the treatment of metastatic melanoma</article-title><source>Semin Oncol</source><year>1997</year><volume>24</volume><fpage>S24</fpage><lpage>S31</lpage><pub-id pub-id-type="pmid">9122731</pub-id></element-citation></ref><ref id="bib11"><label>11.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bukowski</surname><given-names>RM</given-names></name><name><surname>Tendler</surname><given-names>C</given-names></name><name><surname>Cutler</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>Treating cancer with PEG Intron: pharmacokinetic profile and dosing guidelines for an improved interferon-alpha-2b formulation</article-title><source>Cancer</source><year>2002</year><volume>95</volume><fpage>389</fpage><lpage>396</lpage><pub-id pub-id-type="pmid">12124839</pub-id></element-citation></ref><ref id="bib12"><label>12.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dummer</surname><given-names>R</given-names></name><name><surname>Garbe</surname><given-names>C</given-names></name><name><surname>Thompson</surname><given-names>JA</given-names></name><etal></etal></person-group><article-title>Randomized dose-escalation study evaluating peginterferon alfa-2a in patients with metastatic malignant melanoma</article-title><source>J Clin Oncol</source><year>2006</year><volume>24</volume><fpage>1188</fpage><lpage>1194</lpage><pub-id pub-id-type="pmid">16505439</pub-id></element-citation></ref><ref id="bib13"><label>13.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hauschild</surname><given-names>A</given-names></name><name><surname>Dummer</surname><given-names>R</given-names></name><name><surname>Ugurel</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Combined treatment with pegylated interferon-alpha-2a and dacarbazine in patients with advanced metastatic melanoma: a phase 2 study</article-title><source>Cancer</source><year>2008</year><volume>113</volume><fpage>1404</fpage><lpage>1411</lpage><pub-id pub-id-type="pmid">18615619</pub-id></element-citation></ref><ref id="bib14"><label>14.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Spieth</surname><given-names>K</given-names></name><name><surname>Kaufmann</surname><given-names>R</given-names></name><name><surname>Dummer</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Temozolomide plus pegylated interferon alfa-2b as first-line treatment for stage IV melanoma: a multicenter phase II trial of the Dermatologic Cooperative Oncology Group (DeCOG)</article-title><source>Ann Oncol</source><year>2008</year><volume>19</volume><fpage>801</fpage><lpage>806</lpage><pub-id pub-id-type="pmid">18178958</pub-id></element-citation></ref><ref id="bib15"><label>15.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sparano</surname><given-names>JA</given-names></name><name><surname>Fisher</surname><given-names>RI</given-names></name><name><surname>Sunderland</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma</article-title><source>J Clin Oncol</source><year>1993</year><volume>11</volume><fpage>1969</fpage><lpage>1977</lpage><pub-id pub-id-type="pmid">8410122</pub-id></element-citation></ref><ref id="bib16"><label>16.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Marincola</surname><given-names>FM</given-names></name><name><surname>White</surname><given-names>DE</given-names></name><name><surname>Wise</surname><given-names>AP</given-names></name><name><surname>Rosenberg</surname><given-names>SA</given-names></name></person-group><article-title>Combination therapy with interferon alfa-2a and interleukin-2 for the treatment of metastatic cancer</article-title><source>J Clin Oncol</source><year>1995</year><volume>13</volume><fpage>1110</fpage><lpage>1122</lpage><pub-id pub-id-type="pmid">7738617</pub-id></element-citation></ref><ref id="bib17"><label>17.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hamm</surname><given-names>C</given-names></name><name><surname>Verma</surname><given-names>S</given-names></name><name><surname>Petrella</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>Biochemotherapy for the treatment of metastatic malignant melanoma: a systematic review</article-title><source>Cancer Treat Rev</source><year>2008</year><volume>34</volume><fpage>145</fpage><lpage>156</lpage><pub-id pub-id-type="pmid">18077098</pub-id></element-citation></ref><ref id="bib18"><label>18.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ives</surname><given-names>NJ</given-names></name><name><surname>Stowe</surname><given-names>RL</given-names></name><name><surname>Lorigan</surname><given-names>P</given-names></name><name><surname>Wheatley</surname><given-names>K</given-names></name></person-group><article-title>Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients</article-title><source>J Clin Oncol</source><year>2007</year><volume>25</volume><fpage>5426</fpage><lpage>5434</lpage><pub-id pub-id-type="pmid">18048825</pub-id></element-citation></ref><ref id="bib19"><label>19.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Falkson</surname><given-names>CI</given-names></name><name><surname>Falkson</surname><given-names>G</given-names></name><name><surname>Falkson</surname><given-names>HC</given-names></name></person-group><article-title>Improved results with the addition of interferon alfa-2b to dacarbazine in the treatment of patients with metastatic malignant melanoma</article-title><source>J Clin Oncol</source><year>1991</year><volume>9</volume><fpage>1403</fpage><lpage>1408</lpage><pub-id pub-id-type="pmid">2072144</pub-id></element-citation></ref><ref id="bib20"><label>20.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Thomson</surname><given-names>DB</given-names></name><name><surname>Adena</surname><given-names>M</given-names></name><name><surname>McLeod</surname><given-names>GR</given-names></name><etal></etal></person-group><article-title>Interferon-alpha 2a does not improve response or survival when combined with dacarbazine in metastatic malignant melanoma: results of a multi-institutional Australian randomized trial</article-title><source>Melanoma Res</source><year>1993</year><volume>3</volume><fpage>133</fpage><lpage>138</lpage><pub-id pub-id-type="pmid">8518552</pub-id></element-citation></ref><ref id="bib21"><label>21.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bajetta</surname><given-names>E</given-names></name><name><surname>Di Leo</surname><given-names>A</given-names></name><name><surname>Zampino</surname><given-names>MG</given-names></name><etal></etal></person-group><article-title>Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma</article-title><source>J Clin Oncol</source><year>1994</year><volume>12</volume><fpage>806</fpage><lpage>811</lpage><pub-id pub-id-type="pmid">8151323</pub-id></element-citation></ref><ref id="bib22"><label>22.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Falkson</surname><given-names>CI</given-names></name><name><surname>Ibrahim</surname><given-names>J</given-names></name><name><surname>Kirkwood</surname><given-names>JM</given-names></name><etal></etal></person-group><article-title>Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study</article-title><source>J Clin Oncol</source><year>1998</year><volume>16</volume><fpage>1743</fpage><lpage>1751</lpage><pub-id pub-id-type="pmid">9586887</pub-id></element-citation></ref><ref id="bib23"><label>23.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Middleton</surname><given-names>MR</given-names></name><name><surname>Lorigan</surname><given-names>P</given-names></name><name><surname>Owen</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma</article-title><source>Br J Cancer</source><year>2000</year><volume>82</volume><fpage>1158</fpage><lpage>1162</lpage><pub-id pub-id-type="pmid">10735499</pub-id></element-citation></ref><ref id="bib24"><label>24.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Young</surname><given-names>AM</given-names></name><name><surname>Marsden</surname><given-names>J</given-names></name><name><surname>Goodman</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Prospective randomized comparison of dacarbazine (DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in metastatic melanoma</article-title><source>Clin Oncol (R Coll Radiol)</source><year>2001</year><volume>13</volume><fpage>458</fpage><lpage>465</lpage><pub-id pub-id-type="pmid">11824887</pub-id></element-citation></ref><ref id="bib25"><label>25.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kaufmann</surname><given-names>R</given-names></name><name><surname>Spieth</surname><given-names>K</given-names></name><name><surname>Leiter</surname><given-names>U</given-names></name><etal></etal></person-group><article-title>Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group</article-title><source>J Clin Oncol</source><year>2005</year><volume>23</volume><fpage>9001</fpage><lpage>9007</lpage><pub-id pub-id-type="pmid">16260697</pub-id></element-citation></ref><ref id="bib26"><label>26.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vuoristo</surname><given-names>MS</given-names></name><name><surname>Hahka-Kemppinen</surname><given-names>M</given-names></name><name><surname>Parvinen</surname><given-names>LM</given-names></name><etal></etal></person-group><article-title>Randomized trial of dacarbazine versus bleomycin, vincristine, lomustine and dacarbazine (BOLD) chemotherapy combined with natural or recombinant interferon-alpha in patients with advanced melanoma</article-title><source>Melanoma Res</source><year>2005</year><volume>15</volume><fpage>291</fpage><lpage>296</lpage><pub-id pub-id-type="pmid">16034308</pub-id></element-citation></ref><ref id="bib27"><label>27.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Agarwala</surname><given-names>SS</given-names></name><name><surname>Glaspy</surname><given-names>J</given-names></name><name><surname>O'Day</surname><given-names>SJ</given-names></name><etal></etal></person-group><article-title>Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma</article-title><source>J Clin Oncol</source><year>2002</year><volume>20</volume><fpage>125</fpage><lpage>133</lpage><pub-id pub-id-type="pmid">11773161</pub-id></element-citation></ref><ref id="bib28"><label>28.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Keilholz</surname><given-names>U</given-names></name><name><surname>Goey</surname><given-names>SH</given-names></name><name><surname>Punt</surname><given-names>CJ</given-names></name><etal></etal></person-group><article-title>Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group</article-title><source>J Clin Oncol</source><year>1997</year><volume>15</volume><fpage>2579</fpage><lpage>2588</lpage><pub-id pub-id-type="pmid">9215828</pub-id></element-citation></ref><ref id="bib29"><label>29.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Johnston</surname><given-names>SR</given-names></name><name><surname>Constenla</surname><given-names>DO</given-names></name><name><surname>Moore</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Randomized phase II trial of BCDT [carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or without interferon alpha (IFN-alpha) and interleukin (IL-2) in patients with metastatic melanoma</article-title><source>Br J Cancer</source><year>1998</year><volume>77</volume><fpage>1280</fpage><lpage>1286</lpage><pub-id pub-id-type="pmid">9579834</pub-id></element-citation></ref><ref id="bib30"><label>30.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dorval</surname><given-names>T</given-names></name><name><surname>Negrier</surname><given-names>S</given-names></name><name><surname>Chevreau</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Randomized trial of treatment with cisplatin and interleukin-2 either alone or in combination with interferon-alpha-2a in patients with metastatic melanoma: a Federation Nationale des Centres de Lutte Contre le Cancer Multicenter, parallel study</article-title><source>Cancer</source><year>1999</year><volume>85</volume><fpage>1060</fpage><lpage>1066</lpage><pub-id pub-id-type="pmid">10091789</pub-id></element-citation></ref><ref id="bib31"><label>31.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rosenberg</surname><given-names>SA</given-names></name><name><surname>Yang</surname><given-names>JC</given-names></name><name><surname>Schwartzentruber</surname><given-names>DJ</given-names></name><etal></etal></person-group><article-title>Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b</article-title><source>J Clin Oncol</source><year>1999</year><volume>17</volume><fpage>968</fpage><lpage>975</lpage><pub-id pub-id-type="pmid">10071291</pub-id></element-citation></ref><ref id="bib32"><label>32.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hauschild</surname><given-names>A</given-names></name><name><surname>Garbe</surname><given-names>C</given-names></name><name><surname>Stolz</surname><given-names>W</given-names></name><etal></etal></person-group><article-title>Dacarbazine and interferon alpha with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG)</article-title><source>Br J Cancer</source><year>2001</year><volume>84</volume><fpage>1036</fpage><lpage>1042</lpage><pub-id pub-id-type="pmid">11308250</pub-id></element-citation></ref><ref id="bib33"><label>33.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Eton</surname><given-names>O</given-names></name><name><surname>Legha</surname><given-names>SS</given-names></name><name><surname>Bedikian</surname><given-names>AY</given-names></name><etal></etal></person-group><article-title>Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial</article-title><source>J Clin Oncol</source><year>2002</year><volume>20</volume><fpage>2045</fpage><lpage>2052</lpage><pub-id pub-id-type="pmid">11956264</pub-id></element-citation></ref><ref id="bib34"><label>34.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Atzpodien</surname><given-names>J</given-names></name><name><surname>Neuber</surname><given-names>K</given-names></name><name><surname>Kamanabrou</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>Combination chemotherapy with or without s.c. IL-2 and IFN-alpha: results of a prospectively randomized trial of the Cooperative Advanced Malignant Melanoma Chemoimmunotherapy Group (ACIMM)</article-title><source>Br J Cancer</source><year>2002</year><volume>86</volume><fpage>179</fpage><lpage>184</lpage><pub-id pub-id-type="pmid">11870502</pub-id></element-citation></ref><ref id="bib35"><label>35.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ridolfi</surname><given-names>R</given-names></name><name><surname>Chiarion-Sileni</surname><given-names>V</given-names></name><name><surname>Guida</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial</article-title><source>J Clin Oncol</source><year>2002</year><volume>20</volume><fpage>1600</fpage><lpage>1607</lpage><pub-id pub-id-type="pmid">11896110</pub-id></element-citation></ref><ref id="bib36"><label>36.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Keilholz</surname><given-names>U</given-names></name><name><surname>Punt</surname><given-names>CJ</given-names></name><name><surname>Gore</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Dacarbazine, cisplatin, and interferon-alfa-2b with or without interleukin-2 in metastatic melanoma: a randomized phase III trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group</article-title><source>J Clin Oncol</source><year>2005</year><volume>23</volume><fpage>6747</fpage><lpage>6755</lpage><pub-id pub-id-type="pmid">16170182</pub-id></element-citation></ref><ref id="bib37"><label>37.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bajetta</surname><given-names>E</given-names></name><name><surname>Del Vecchio</surname><given-names>M</given-names></name><name><surname>Nova</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma</article-title><source>Ann Oncol</source><year>2006</year><volume>17</volume><fpage>571</fpage><lpage>577</lpage><pub-id pub-id-type="pmid">16469753</pub-id></element-citation></ref><ref id="bib38"><label>38.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Atkins</surname><given-names>MB</given-names></name><name><surname>Hsu</surname><given-names>J</given-names></name><name><surname>Lee</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group</article-title><source>J Clin Oncol</source><year>2008</year><volume>26</volume><fpage>5748</fpage><lpage>5754</lpage><pub-id pub-id-type="pmid">19001327</pub-id></element-citation></ref><ref id="bib39"><label>39.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Davis</surname><given-names>ID</given-names></name><name><surname>Skak</surname><given-names>K</given-names></name><name><surname>Smyth</surname><given-names>MJ</given-names></name><etal></etal></person-group><article-title>Interleukin-21 signaling: functions in cancer and autoimmunity</article-title><source>Clin Cancer Res</source><year>2007</year><volume>13</volume><fpage>6926</fpage><lpage>6932</lpage><pub-id pub-id-type="pmid">18056166</pub-id></element-citation></ref><ref id="bib40"><label>40.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fehniger</surname><given-names>TA</given-names></name><name><surname>Cooper</surname><given-names>MA</given-names></name><name><surname>Caligiuri</surname><given-names>MA</given-names></name></person-group><article-title>Interleukin-2 and interleukin-15: immunotherapy for cancer</article-title><source>Cytokine Growth Factor Rev</source><year>2002</year><volume>13</volume><fpage>169</fpage><lpage>183</lpage><pub-id pub-id-type="pmid">11900992</pub-id></element-citation></ref><ref id="bib41"><label>41.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Thompson</surname><given-names>JA</given-names></name><name><surname>Curti</surname><given-names>BD</given-names></name><name><surname>Redman</surname><given-names>BG</given-names></name><etal></etal></person-group><article-title>Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma</article-title><source>J Clin Oncol</source><year>2008</year><volume>26</volume><fpage>2034</fpage><lpage>2039</lpage><pub-id pub-id-type="pmid">18347008</pub-id></element-citation></ref><ref id="bib42"><label>42.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Frederiksen</surname><given-names>KS</given-names></name><name><surname>Lundsgaard</surname><given-names>D</given-names></name><name><surname>Freeman</surname><given-names>JA</given-names></name><etal></etal></person-group><article-title>IL-21 induces in vivo immune activation of NK cells and CD8(+) T cells in patients with metastatic melanoma and renal cell carcinoma</article-title><source>Cancer Immunol Immunother</source><year>2008</year><volume>57</volume><fpage>1439</fpage><lpage>1449</lpage><pub-id pub-id-type="pmid">18286285</pub-id></element-citation></ref><ref id="bib43"><label>43.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Inman</surname><given-names>BA</given-names></name><name><surname>Frigola</surname><given-names>X</given-names></name><name><surname>Dong</surname><given-names>H</given-names></name><name><surname>Kwon</surname><given-names>ED</given-names></name></person-group><article-title>Costimulation, coinhibition and cancer</article-title><source>Curr Cancer Drug Targets</source><year>2007</year><volume>7</volume><fpage>15</fpage><lpage>30</lpage><pub-id pub-id-type="pmid">17305475</pub-id></element-citation></ref><ref id="bib44"><label>44.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Melero</surname><given-names>I</given-names></name><name><surname>Hervas-Stubbs</surname><given-names>S</given-names></name><name><surname>Glennie</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Immunostimulatory monoclonal antibodies for cancer therapy</article-title><source>Nat Rev Cancer</source><year>2007</year><volume>7</volume><fpage>95</fpage><lpage>106</lpage><pub-id pub-id-type="pmid">17251916</pub-id></element-citation></ref><ref id="bib45"><label>45.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>O'Day</surname><given-names>SJ</given-names></name><name><surname>Hamid</surname><given-names>O</given-names></name><name><surname>Urba</surname><given-names>WJ</given-names></name></person-group><article-title>Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies</article-title><source>Cancer</source><year>2007</year><volume>110</volume><fpage>2614</fpage><lpage>2627</lpage><pub-id pub-id-type="pmid">18000991</pub-id></element-citation></ref><ref id="bib46"><label>46.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cranmer</surname><given-names>LD</given-names></name><name><surname>Hersh</surname><given-names>E</given-names></name></person-group><article-title>The role of the CTLA4 blockade in the treatment of malignant melanoma</article-title><source>Cancer Invest</source><year>2007</year><volume>25</volume><fpage>613</fpage><lpage>631</lpage><pub-id pub-id-type="pmid">18027152</pub-id></element-citation></ref><ref id="bib47"><label>47.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Weber</surname><given-names>J</given-names></name></person-group><article-title>Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events</article-title><source>Oncologist</source><year>2007</year><volume>12</volume><fpage>864</fpage><lpage>872</lpage><pub-id pub-id-type="pmid">17673617</pub-id></element-citation></ref><ref id="bib48"><label>48.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ribas</surname><given-names>A</given-names></name><name><surname>Hanson</surname><given-names>DC</given-names></name><name><surname>Noe</surname><given-names>DA</given-names></name><etal></etal></person-group><article-title>Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer</article-title><source>Oncologist</source><year>2007</year><volume>12</volume><fpage>873</fpage><lpage>883</lpage><pub-id pub-id-type="pmid">17673618</pub-id></element-citation></ref><ref id="bib49"><label>49.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hersh</surname><given-names>EM</given-names></name><name><surname>Weber</surname><given-names>JS</given-names></name><name><surname>Powderly</surname><given-names>JD</given-names></name><etal></etal></person-group><article-title>Disease control and long-term survival in chemotherapy-naive patients with advanced melanoma treated with ipilimumab (MDX- 010) with or without dacarbazine. 2008 ASCO Annual proceedings Part I</article-title><source>J Clin Oncol</source><year>2008</year><volume>26</volume><comment>Abstr 9022</comment></element-citation></ref><ref id="bib50"><label>50.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Attia</surname><given-names>P</given-names></name><name><surname>Phan</surname><given-names>GQ</given-names></name><name><surname>Maker</surname><given-names>AV</given-names></name><etal></etal></person-group><article-title>Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4</article-title><source>J Clin Oncol</source><year>2005</year><volume>23</volume><fpage>6043</fpage><lpage>6053</lpage><pub-id pub-id-type="pmid">16087944</pub-id></element-citation></ref><ref id="bib51"><label>51.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Downey</surname><given-names>SG</given-names></name><name><surname>Klapper</surname><given-names>JA</given-names></name><name><surname>Smith</surname><given-names>FO</given-names></name><etal></etal></person-group><article-title>Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade</article-title><source>Clin Cancer Res</source><year>2007</year><volume>13</volume><fpage>6681</fpage><lpage>6688</lpage><pub-id pub-id-type="pmid">17982122</pub-id></element-citation></ref><ref id="bib52"><label>52.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Beck</surname><given-names>KE</given-names></name><name><surname>Blansfield</surname><given-names>JA</given-names></name><name><surname>Tran</surname><given-names>KQ</given-names></name><etal></etal></person-group><article-title>Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4</article-title><source>J Clin Oncol</source><year>2006</year><volume>24</volume><fpage>2283</fpage><lpage>2289</lpage><pub-id pub-id-type="pmid">16710025</pub-id></element-citation></ref><ref id="bib53"><label>53.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hamid</surname><given-names>O</given-names></name><name><surname>Chin</surname><given-names>K</given-names></name><name><surname>Li</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Dose effect of ipilimumab in patients with advanced melanoma: Results from a phase II, randomized, dose-ranging study. 2008 ASCO Annual proceedings Part I</article-title><source>J Clin Oncol</source><year>2008</year><volume>26</volume><comment>Abstr 9025</comment></element-citation></ref><ref id="bib54"><label>54.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>O'Day</surname><given-names>SJ</given-names></name><name><surname>Ibrahim</surname><given-names>R</given-names></name><name><surname>DePril</surname><given-names>V</given-names></name><etal></etal></person-group><article-title>Efficacy and safety of ipilimumab induction and maintenance dosing in patients with advanced melanoma who progressed on one or more prior therapies. ASCO Annual proceedings Part I</article-title><source>J Clin Oncol</source><year>2008</year><volume>26</volume><comment>Abstr 9021</comment></element-citation></ref><ref id="bib55"><label>55.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wolchok</surname><given-names>JD</given-names></name><name><surname>Ibrahim</surname><given-names>R</given-names></name><name><surname>DePril</surname><given-names>V</given-names></name><etal></etal></person-group><article-title>Antitumor response and new lesions in advanced melanoma patients on ipilimumab treatment. ASCO Annual proceedings Part I</article-title><source>J Clin Oncol</source><year>2008</year><volume>26</volume><comment>Abstr 3020</comment></element-citation></ref><ref id="bib56"><label>56.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hodi</surname><given-names>FS</given-names></name><name><surname>Hoos</surname><given-names>A</given-names></name><name><surname>Ibrahim</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Novel efficacy criteria for antitumor activity to immunotherapy using the example of ipilimumab, an anti-CTLA-4 monoclonal antibody. ASCO Annual Proceedings Part I</article-title><source>J Clin Oncol</source><year>2008</year><volume>26</volume><comment>Abstr 3008</comment></element-citation></ref><ref id="bib57"><label>57.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ribas</surname><given-names>A</given-names></name><name><surname>Antonia</surname><given-names>S</given-names></name><name><surname>Sosman</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Results of a phase II clinical trial of 2 doses and schedules of CP-675,206, an anti-CTLA4 monoclonal antibody, in patients (pts) with advanced melanoma. ASCO Annual Meeting Proceedings Part I</article-title><source>J Clin Oncol</source><year>2007</year><volume>25</volume><comment>Abstr 3000</comment></element-citation></ref><ref id="bib58"><label>58.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gomez-Navarro</surname><given-names>J</given-names></name><name><surname>Antonia</surname><given-names>S</given-names></name><name><surname>Sosman</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Survival of patients (pts) with metastatic melanoma treated with the anti-CTLA4 monoclonal antibody (mAb) CP-675,206 in a phase I/II study. ASCO Annual Meeting Proceedings Part I</article-title><source>J Clin Oncol</source><year>2007</year><volume>26</volume><comment>Abstr 8524</comment></element-citation></ref><ref id="bib59"><label>59.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kirkwood</surname><given-names>JM</given-names></name><name><surname>Lorigan</surname><given-names>P</given-names></name><name><surname>Hersey</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>A phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. ASCO Annual proceedings Part I</article-title><source>J Clin Oncol</source><year>2008</year><volume>26</volume><comment>Abstr 9023</comment></element-citation></ref><ref id="bib60"><label>60.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ribas</surname><given-names>A</given-names></name><name><surname>Hauschild</surname><given-names>A</given-names></name><name><surname>Kefford</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Phase III, open-label, randomized, comparative study of tremelimumab (CP-675,206) and chemotherapy (temozolomide [TMZ] or dacarbazine [DTIC]) in patients with advanced melanoma. 2008 ASCO Annual proceedings Part I</article-title><source>J Clin Oncol</source><year>2008</year><volume>26</volume><comment>Abstr LBA9011</comment></element-citation></ref><ref id="bib61"><label>61.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tarhini</surname><given-names>AA</given-names></name><name><surname>Moschos</surname><given-names>SS</given-names></name><name><surname>Schlesselman</surname><given-names>JJ</given-names></name><etal></etal></person-group><article-title>Phase II trial of combination biotherapy of high-dose interferon alfa-2b and tremelimumab for recurrent inoperable stage III or stage IV melanoma. 2008 ASCO Annual proceedings Part I</article-title><source>J Clin Oncol</source><year>2008</year><volume>26</volume><comment>Abstr 9009</comment></element-citation></ref><ref id="bib62"><label>62.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Li</surname><given-names>B</given-names></name><name><surname>Lin</surname><given-names>J</given-names></name><name><surname>Vanroey</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Established B16 tumors are rejected following treatment with GM-CSF-secreting tumor cell immunotherapy in combination with anti-4-1BB mAb</article-title><source>Clin Immunol</source><year>2007</year><volume>125</volume><fpage>76</fpage><lpage>87</lpage><pub-id pub-id-type="pmid">17706463</pub-id></element-citation></ref><ref id="bib63"><label>63.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Choi</surname><given-names>BK</given-names></name><name><surname>Kim</surname><given-names>YH</given-names></name><name><surname>Kang</surname><given-names>WJ</given-names></name><etal></etal></person-group><article-title>Mechanisms involved in synergistic anticancer immunity of anti-4-1BB and anti-CD4 therapy</article-title><source>Cancer Res</source><year>2007</year><volume>67</volume><fpage>8891</fpage><lpage>8899</lpage><pub-id pub-id-type="pmid">17875731</pub-id></element-citation></ref><ref id="bib64"><label>64.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sznol</surname><given-names>M</given-names></name><name><surname>Hodi</surname><given-names>FS</given-names></name><name><surname>Margolin</surname><given-names>K</given-names></name><etal></etal></person-group><article-title>Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA). 2008 ASCO Annual proceedings Part I</article-title><source>J Clin Oncol</source><year>2008</year><volume>26</volume><comment>Abstr 3007</comment></element-citation></ref><ref id="bib65"><label>65.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Trikha</surname><given-names>M</given-names></name><name><surname>Zhou</surname><given-names>Z</given-names></name><name><surname>Nemeth</surname><given-names>JA</given-names></name><etal></etal></person-group><article-title>CNTO 95, a fully human monoclonal antibody that inhibits alphav integrins, has antitumor and antiangiogenic activity in vivo</article-title><source>Int J Cancer</source><year>2004</year><volume>110</volume><fpage>326</fpage><lpage>335</lpage><pub-id pub-id-type="pmid">15095296</pub-id></element-citation></ref><ref id="bib66"><label>66.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jayson</surname><given-names>GC</given-names></name><name><surname>Mullamitha</surname><given-names>S</given-names></name><name><surname>Ton</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Phase I study of CNTO 95, a fully human monoclonal antibody (mAb) to av integrins, in patients with solid tumors. 2005 ASCO Annual Meeting Proceedings Part I</article-title><source>J Clin Oncol</source><year>2005</year><volume>23</volume><comment>Abstr 3113</comment></element-citation></ref><ref id="bib67"><label>67.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cranmer</surname><given-names>LD</given-names></name><name><surname>Bedikian</surname><given-names>AY</given-names></name><name><surname>Ribas</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Phase II study of volociximab (M200), an α5β1 anti-integrin antibody in metastatic melanoma. 2005 ASCO Annual Meeting Proceedings Part I</article-title><source>J Clin Oncol</source><year>2005</year><volume>24</volume><comment>Abstr 8011</comment></element-citation></ref><ref id="bib68"><label>68.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Linette</surname><given-names>G</given-names></name><name><surname>Cranmer</surname><given-names>L</given-names></name><name><surname>Hodi</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>A multicenter phase II study of volociximab in patients with relapsed metastatic melanoma. 2008 ASCO Annual proceedings Part I</article-title><source>J Clin Oncol</source><year>2008</year><fpage>26</fpage><comment>Abstr 3505</comment><pub-id pub-id-type="pmid">18165637</pub-id></element-citation></ref><ref id="bib69"><label>69.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mulgrew</surname><given-names>K</given-names></name><name><surname>Kinneer</surname><given-names>K</given-names></name><name><surname>Yao</surname><given-names>XT</given-names></name><etal></etal></person-group><article-title>Direct targeting of alphavbeta3 integrin on tumor cells with a monoclonal antibody</article-title><source>Abegrin. Mol Cancer Ther</source><year>2006</year><volume>5</volume><fpage>3122</fpage><lpage>3129</lpage></element-citation></ref><ref id="bib70"><label>70.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hersey</surname><given-names>P</given-names></name><name><surname>Sosman</surname><given-names>J</given-names></name><name><surname>O'Day</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>A phase II, randomized, open-label study evaluating the antitumor activity of MEDI-522, a humanized monoclonal antibody directed against the human alpha v beta 3 (avb3) integrin, ± dacarbazine (DTIC) in patients with metastatic melanoma (MM). 2005 ASCO Annual Meeting Proceedings Part I</article-title><source>J Clin Oncol</source><year>2005</year><volume>23</volume><comment>Abstr 7507</comment></element-citation></ref><ref id="bib71"><label>71.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rosenberg</surname><given-names>SA</given-names></name><name><surname>Yang</surname><given-names>JC</given-names></name><name><surname>Restifo</surname><given-names>NP</given-names></name></person-group><article-title>Cancer immunotherapy: moving beyond current vaccines</article-title><source>Nat Med</source><year>2004</year><volume>10</volume><fpage>909</fpage><lpage>915</lpage><pub-id pub-id-type="pmid">15340416</pub-id></element-citation></ref><ref id="bib72"><label>72.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sondak</surname><given-names>VK</given-names></name><name><surname>Sabel</surname><given-names>MS</given-names></name><name><surname>Mule</surname><given-names>JJ</given-names></name></person-group><article-title>Allogeneic and autologous melanoma vaccines: where have we been and where are we going?</article-title><source>Clin Cancer Res</source><year>2006</year><volume>12</volume><fpage>2337s</fpage><lpage>2341s</lpage><pub-id pub-id-type="pmid">16609055</pub-id></element-citation></ref><ref id="bib73"><label>73.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morton</surname><given-names>DL</given-names></name><name><surname>Mozzillo</surname><given-names>N</given-names></name><name><surname>Thompson</surname><given-names>JF</given-names></name><etal></etal></person-group><article-title>An international, randomized, phase III trial of bacillus Calmette-Guerin (BCG) plus allogeneic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites. 2007 ASCO Annual Meeting Proceedings Part I</article-title><source>J Clin Oncol</source><year>2007</year><volume>25</volume><comment>Abstr 8508</comment></element-citation></ref><ref id="bib74"><label>74.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Srivastava</surname><given-names>P</given-names></name></person-group><article-title>Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses</article-title><source>Annu Rev Immunol</source><year>2002</year><volume>20</volume><fpage>395</fpage><lpage>425</lpage><pub-id pub-id-type="pmid">11861608</pub-id></element-citation></ref><ref id="bib75"><label>75.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Belli</surname><given-names>F</given-names></name><name><surname>Testori</surname><given-names>A</given-names></name><name><surname>Rivoltini</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Vaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: clinical and immunologic findings</article-title><source>J Clin Oncol</source><year>2002</year><volume>20</volume><fpage>4169</fpage><lpage>4180</lpage><pub-id pub-id-type="pmid">12377960</pub-id></element-citation></ref><ref id="bib76"><label>76.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Testori</surname><given-names>A</given-names></name><name><surname>Richards</surname><given-names>J</given-names></name><name><surname>Whitman</surname><given-names>E</given-names></name><etal></etal></person-group><article-title>Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group</article-title><source>J Clin Oncol</source><year>2008</year><volume>26</volume><fpage>955</fpage><lpage>962</lpage><pub-id pub-id-type="pmid">18281670</pub-id></element-citation></ref><ref id="bib77"><label>77.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Coulie</surname><given-names>PG</given-names></name><name><surname>Karanikas</surname><given-names>V</given-names></name><name><surname>Colau</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>A monoclonal cytolytic T-lymphocyte response observed in a melanoma patient vaccinated with a tumor-specific antigenic peptide encoded by gene MAGE-3</article-title><source>Proc Natl Acad Sci USA</source><year>2001</year><volume>98</volume><fpage>10290</fpage><lpage>10295</lpage><pub-id pub-id-type="pmid">11517302</pub-id></element-citation></ref><ref id="bib78"><label>78.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kruit</surname><given-names>WH</given-names></name><name><surname>Suciu</surname><given-names>S</given-names></name><name><surname>Dreno</surname><given-names>B</given-names></name><etal></etal></person-group><article-title>Immunization with recombinant MAGE-A3 protein combined with adjuvant systems AS15 or AS02B in patients with unresectable and progressive metastatic cutaneous melanoma: a randomized open-label phase II study of the EORTC Melanoma Group (16032-18031). 2008 ASCO Annual Proceedings Part I</article-title><source>J Clin Oncol</source><year>2008</year><volume>26</volume><comment>Abstr 9065</comment></element-citation></ref><ref id="bib79"><label>79.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Purcell</surname><given-names>AW</given-names></name><name><surname>McCluskey</surname><given-names>J</given-names></name><name><surname>Rossjohn</surname><given-names>J</given-names></name></person-group><article-title>More than one reason to rethink the use of peptides in vaccine design</article-title><source>Nat Rev Drug Discov</source><year>2007</year><volume>6</volume><fpage>404</fpage><lpage>414</lpage><pub-id pub-id-type="pmid">17473845</pub-id></element-citation></ref><ref id="bib80"><label>80.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Melief</surname><given-names>CJ</given-names></name><name><surname>van der Burg</surname><given-names>SH</given-names></name></person-group><article-title>Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines</article-title><source>Nat Rev Cancer</source><year>2008</year><volume>8</volume><fpage>351</fpage><lpage>360</lpage><pub-id pub-id-type="pmid">18418403</pub-id></element-citation></ref><ref id="bib81"><label>81.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Osada</surname><given-names>T</given-names></name><name><surname>Clay</surname><given-names>TM</given-names></name><name><surname>Woo</surname><given-names>CY</given-names></name><etal></etal></person-group><article-title>Dendritic cell-based immunotherapy</article-title><source>Int Rev Immunol</source><year>2006</year><volume>25</volume><fpage>377</fpage><lpage>413</lpage><pub-id pub-id-type="pmid">17169781</pub-id></element-citation></ref><ref id="bib82"><label>82.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Thurner</surname><given-names>B</given-names></name><name><surname>Haendle</surname><given-names>I</given-names></name><name><surname>Roder</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma</article-title><source>J Exp Med</source><year>1999</year><volume>190</volume><fpage>1669</fpage><lpage>1678</lpage><pub-id pub-id-type="pmid">10587357</pub-id></element-citation></ref><ref id="bib83"><label>83.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schadendorf</surname><given-names>D</given-names></name><name><surname>Ugurel</surname><given-names>S</given-names></name><name><surname>Schuler-Thurner</surname><given-names>B</given-names></name><etal></etal></person-group><article-title>Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG</article-title><source>Ann Oncol</source><year>2006</year><volume>17</volume><fpage>563</fpage><lpage>570</lpage><pub-id pub-id-type="pmid">16418308</pub-id></element-citation></ref><ref id="bib84"><label>84.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lesterhuis</surname><given-names>WJ</given-names></name><name><surname>Aarntzen</surname><given-names>EH</given-names></name><name><surname>De Vries</surname><given-names>IJ</given-names></name><etal></etal></person-group><article-title>Dendritic cell vaccines in melanoma: from promise to proof?</article-title><source>Crit Rev Oncol Hematol</source><year>2008</year><volume>66</volume><fpage>118</fpage><lpage>134</lpage><pub-id pub-id-type="pmid">18262431</pub-id></element-citation></ref><ref id="bib85"><label>85.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lens</surname><given-names>M</given-names></name></person-group><article-title>The role of vaccine therapy in the treatment of melanoma</article-title><source>Expert Opin Biol Ther</source><year>2008</year><volume>8</volume><fpage>315</fpage><lpage>323</lpage><pub-id pub-id-type="pmid">18294102</pub-id></element-citation></ref><ref id="bib86"><label>86.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dummer</surname><given-names>R</given-names></name><name><surname>Rochlitz</surname><given-names>C</given-names></name><name><surname>Velu</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>Intralesional adenovirus-mediated interleukin-2 gene transfer for advanced solid cancers and melanoma</article-title><source>Mol Ther</source><year>2008</year><volume>16</volume><fpage>985</fpage><lpage>994</lpage><pub-id pub-id-type="pmid">18388930</pub-id></element-citation></ref><ref id="bib87"><label>87.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Heinzerling</surname><given-names>L</given-names></name><name><surname>Burg</surname><given-names>G</given-names></name><name><surname>Dummer</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Intratumoral injection of DNA encoding human interleukin 12 into patients with metastatic melanoma: clinical efficacy</article-title><source>Hum Gene Ther</source><year>2005</year><volume>16</volume><fpage>35</fpage><lpage>48</lpage><pub-id pub-id-type="pmid">15703487</pub-id></element-citation></ref><ref id="bib88"><label>88.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mahvi</surname><given-names>DM</given-names></name><name><surname>Henry</surname><given-names>MB</given-names></name><name><surname>Albertini</surname><given-names>MR</given-names></name><etal></etal></person-group><article-title>Intratumoral injection of IL-12 plasmid DNA—results of a phase I/IB clinical trial</article-title><source>Cancer Gene Ther</source><year>2007</year><volume>14</volume><fpage>717</fpage><lpage>723</lpage><pub-id pub-id-type="pmid">17557109</pub-id></element-citation></ref><ref id="bib89"><label>89.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Senzer</surname><given-names>NN</given-names></name><name><surname>Kaufman</surname><given-names>HL</given-names></name><name><surname>Amatruda</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>Phase II clinical trial with a second generation, GM-CSF encoding, oncolytic herpesvirus in unresectable metastatic melanoma. 2008 ASCO Annual proceedings Part I</article-title><source>J Clin Oncol</source><year>2008</year><volume>26</volume><comment>Abstr 9008</comment></element-citation></ref><ref id="bib90"><label>90.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gattinoni</surname><given-names>L</given-names></name><name><surname>Powell</surname><given-names>DJ</given-names><suffix>Jr</suffix></name><name><surname>Rosenberg</surname><given-names>SA</given-names></name><name><surname>Restifo</surname><given-names>NP</given-names></name></person-group><article-title>Adoptive immunotherapy for cancer: building on success</article-title><source>Nat Rev Immunol</source><year>2006</year><volume>6</volume><fpage>383</fpage><lpage>393</lpage><pub-id pub-id-type="pmid">16622476</pub-id></element-citation></ref><ref id="bib91"><label>91.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mule</surname><given-names>JJ</given-names></name><name><surname>Shu</surname><given-names>S</given-names></name><name><surname>Schwarz</surname><given-names>SL</given-names></name><name><surname>Rosenberg</surname><given-names>SA</given-names></name></person-group><article-title>Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2</article-title><source>Science</source><year>1984</year><volume>225</volume><fpage>1487</fpage><lpage>1489</lpage><pub-id pub-id-type="pmid">6332379</pub-id></element-citation></ref><ref id="bib92"><label>92.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rosenberg</surname><given-names>SA</given-names></name><name><surname>Spiess</surname><given-names>P</given-names></name><name><surname>Lafreniere</surname><given-names>R</given-names></name></person-group><article-title>A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes</article-title><source>Science</source><year>1986</year><volume>233</volume><fpage>1318</fpage><lpage>1321</lpage><pub-id pub-id-type="pmid">3489291</pub-id></element-citation></ref><ref id="bib93"><label>93.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rosenberg</surname><given-names>SA</given-names></name><name><surname>Yannelli</surname><given-names>JR</given-names></name><name><surname>Yang</surname><given-names>JC</given-names></name><etal></etal></person-group><article-title>Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2</article-title><source>J Natl Cancer Inst</source><year>1994</year><volume>86</volume><fpage>1159</fpage><lpage>1166</lpage><pub-id pub-id-type="pmid">8028037</pub-id></element-citation></ref><ref id="bib94"><label>94.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dudley</surname><given-names>ME</given-names></name><name><surname>Wunderlich</surname><given-names>JR</given-names></name><name><surname>Robbins</surname><given-names>PF</given-names></name><etal></etal></person-group><article-title>Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes</article-title><source>Science</source><year>2002</year><volume>298</volume><fpage>850</fpage><lpage>854</lpage><pub-id pub-id-type="pmid">12242449</pub-id></element-citation></ref><ref id="bib95"><label>95.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mackensen</surname><given-names>A</given-names></name><name><surname>Meidenbauer</surname><given-names>N</given-names></name><name><surname>Vogl</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Phase I study of adoptive T-cell therapy using antigen-specific CD8+ T cells for the treatment of patients with metastatic melanoma</article-title><source>J Clin Oncol</source><year>2006</year><volume>24</volume><fpage>5060</fpage><lpage>5069</lpage><pub-id pub-id-type="pmid">17075125</pub-id></element-citation></ref><ref id="bib96"><label>96.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Powell</surname><given-names>DJ</given-names><suffix>Jr</suffix></name><name><surname>Dudley</surname><given-names>ME</given-names></name><name><surname>Hogan</surname><given-names>KA</given-names></name><etal></etal></person-group><article-title>Adoptive transfer of vaccine-induced peripheral blood mononuclear cells to patients with metastatic melanoma following lymphodepletion</article-title><source>J Immunol</source><year>2006</year><volume>177</volume><fpage>6527</fpage><lpage>6539</lpage><pub-id pub-id-type="pmid">17056585</pub-id></element-citation></ref><ref id="bib97"><label>97.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hunder</surname><given-names>NN</given-names></name><name><surname>Wallen</surname><given-names>H</given-names></name><name><surname>Cao</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1</article-title><source>N Engl J Med</source><year>2008</year><volume>358</volume><fpage>2698</fpage><lpage>2703</lpage><pub-id pub-id-type="pmid">18565862</pub-id></element-citation></ref><ref id="bib98"><label>98.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dudley</surname><given-names>ME</given-names></name><name><surname>Wunderlich</surname><given-names>JR</given-names></name><name><surname>Yang</surname><given-names>JC</given-names></name><etal></etal></person-group><article-title>Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma</article-title><source>J Clin Oncol</source><year>2005</year><volume>23</volume><fpage>2346</fpage><lpage>2357</lpage><pub-id pub-id-type="pmid">15800326</pub-id></element-citation></ref><ref id="bib99"><label>99.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rosenberg</surname><given-names>SA</given-names></name><name><surname>Restifo</surname><given-names>NP</given-names></name><name><surname>Yang</surname><given-names>JC</given-names></name><etal></etal></person-group><article-title>Adoptive cell transfer: a clinical path to effective cancer immunotherapy</article-title><source>Nat Rev Cancer</source><year>2008</year><volume>8</volume><fpage>299</fpage><lpage>308</lpage><pub-id pub-id-type="pmid">18354418</pub-id></element-citation></ref><ref id="bib100"><label>100.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morgan</surname><given-names>RA</given-names></name><name><surname>Dudley</surname><given-names>ME</given-names></name><name><surname>Wunderlich</surname><given-names>JR</given-names></name><etal></etal></person-group><article-title>Cancer regression in patients after transfer of genetically engineered lymphocytes</article-title><source>Science</source><year>2006</year><volume>314</volume><fpage>126</fpage><lpage>129</lpage><pub-id pub-id-type="pmid">16946036</pub-id></element-citation></ref><ref id="bib101"><label>101.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tran</surname><given-names>KQ</given-names></name><name><surname>Zhou</surname><given-names>J</given-names></name><name><surname>Durflinger</surname><given-names>KH</given-names></name><etal></etal></person-group><article-title>Minimally cultured tumor-infiltrating lymphocytes display optimal characteristics for adoptive cell therapy</article-title><source>J Immunother</source><year>2008</year><volume>31</volume><fpage>742</fpage><lpage>751</lpage><pub-id pub-id-type="pmid">18779745</pub-id></element-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Asie/explor/AustralieFrV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 0022419 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 0022419 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Asie
|area= AustralieFrV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé=
|texte=
}}
| This area was generated with Dilib version V0.6.33. |  |