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Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE)

Identifieur interne : 000076 ( Main/Exploration ); précédent : 000075; suivant : 000077

Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE)

Auteurs : Philip George [Nouvelle-Zélande] ; Nathaniel Dasyam [Nouvelle-Zélande] ; Giulia Giunti [Nouvelle-Zélande] ; Brigitta Mester [Nouvelle-Zélande] ; Evelyn Bauer [Nouvelle-Zélande] ; Bethany Andrews [Nouvelle-Zélande] ; Travis Perera [Nouvelle-Zélande] ; Tess Ostapowicz [Nouvelle-Zélande] ; Chris Frampton [Nouvelle-Zélande] ; Peng Li [République populaire de Chine] ; David Ritchie [Australie] ; Catherine M. Bollard [États-Unis] ; Ian F. Hermans [Nouvelle-Zélande] ; Robert Weinkove [Nouvelle-Zélande]

Source :

RBID : PMC:7044946

Abstract

Introduction

Autologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r/r B-NHL.

Methods and analysis

Eligible participants will be adults with r/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2 days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3 dose escalation scheme is planned starting at 5×104 CAR T-cells/kg with a maximum dose of 1×106 CAR T-cells/kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy.

Ethics and dissemination

Ethical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19/STH/69) on 23 June 2019 for Protocol V.1.2. Trial results will be reported in a peer-reviewed journal, and results presented at scientific conferences or meetings.

Trial registration number

NCT04049513


Url:
DOI: 10.1136/bmjopen-2019-034629
PubMed: 32041862
PubMed Central: 7044946


Affiliations:

Links toward previous steps (curation, corpus...)

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,
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,
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,
<country>China</country>
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<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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</author>
<author>
<name sortKey="Hermans, Ian F" sort="Hermans, Ian F" uniqKey="Hermans I" first="Ian F" last="Hermans">Ian F. Hermans</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">
<institution content-type="department">Cancer Immunotherapy Programme</institution>
,
<institution>Malaghan Institute of Medical Research</institution>
,
<addr-line content-type="city">Wellington</addr-line>
,
<country>New Zealand</country>
</nlm:aff>
<country xml:lang="fr">Nouvelle-Zélande</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff7">
<institution>Maurice Wilkins Centre for Molecular Biodiscovery</institution>
,
<addr-line content-type="city">Auckland</addr-line>
,
<country>New Zealand</country>
</nlm:aff>
<country xml:lang="fr">Nouvelle-Zélande</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Weinkove, Robert" sort="Weinkove, Robert" uniqKey="Weinkove R" first="Robert" last="Weinkove">Robert Weinkove</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">
<institution content-type="department">Cancer Immunotherapy Programme</institution>
,
<institution>Malaghan Institute of Medical Research</institution>
,
<addr-line content-type="city">Wellington</addr-line>
,
<country>New Zealand</country>
</nlm:aff>
<country xml:lang="fr">Nouvelle-Zélande</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff2">
<institution content-type="department">Wellington Blood and Cancer Centre</institution>
,
<institution>Wellington Hospital</institution>
,
<addr-line content-type="city">Newtown</addr-line>
,
<addr-line content-type="state">Wellington</addr-line>
,
<country>New Zealand</country>
</nlm:aff>
<country xml:lang="fr">Nouvelle-Zélande</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series>
<title level="j">BMJ Open</title>
<idno type="eISSN">2044-6055</idno>
<imprint>
<date when="2020">2020</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<sec>
<title>Introduction</title>
<p>Autologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r/r B-NHL.</p>
</sec>
<sec>
<title>Methods and analysis</title>
<p>Eligible participants will be adults with r/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2 days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3 dose escalation scheme is planned starting at 5×10
<sup>4</sup>
 CAR T-cells/kg with a maximum dose of 1×10
<sup>6</sup>
 CAR T-cells/kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy.</p>
</sec>
<sec>
<title>Ethics and dissemination</title>
<p>Ethical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19/STH/69) on 23 June 2019 for Protocol V.1.2. Trial results will be reported in a peer-reviewed journal, and results presented at scientific conferences or meetings.</p>
</sec>
<sec>
<title>Trial registration number</title>
<p>
<ext-link ext-link-type="uri" xlink:href="NCT04049513" specific-use="clinicaltrial pre-results">NCT04049513</ext-link>
</p>
</sec>
</div>
</front>
<back>
<div1 type="bibliography">
<listBibl>
<biblStruct>
<analytic>
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<analytic>
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<biblStruct>
<analytic>
<author>
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<biblStruct>
<analytic>
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<biblStruct>
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<biblStruct>
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<biblStruct>
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<biblStruct>
<analytic>
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<biblStruct>
<analytic>
<author>
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<biblStruct>
<analytic>
<author>
<name sortKey="Turtle, Cj" uniqKey="Turtle C">CJ Turtle</name>
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<author>
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<name sortKey="Berger, C" uniqKey="Berger C">C Berger</name>
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<biblStruct>
<analytic>
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</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<affiliations>
<list>
<country>
<li>Australie</li>
<li>Nouvelle-Zélande</li>
<li>République populaire de Chine</li>
<li>États-Unis</li>
</country>
</list>
<tree>
<country name="Nouvelle-Zélande">
<noRegion>
<name sortKey="George, Philip" sort="George, Philip" uniqKey="George P" first="Philip" last="George">Philip George</name>
</noRegion>
<name sortKey="Andrews, Bethany" sort="Andrews, Bethany" uniqKey="Andrews B" first="Bethany" last="Andrews">Bethany Andrews</name>
<name sortKey="Bauer, Evelyn" sort="Bauer, Evelyn" uniqKey="Bauer E" first="Evelyn" last="Bauer">Evelyn Bauer</name>
<name sortKey="Dasyam, Nathaniel" sort="Dasyam, Nathaniel" uniqKey="Dasyam N" first="Nathaniel" last="Dasyam">Nathaniel Dasyam</name>
<name sortKey="Frampton, Chris" sort="Frampton, Chris" uniqKey="Frampton C" first="Chris" last="Frampton">Chris Frampton</name>
<name sortKey="Giunti, Giulia" sort="Giunti, Giulia" uniqKey="Giunti G" first="Giulia" last="Giunti">Giulia Giunti</name>
<name sortKey="Hermans, Ian F" sort="Hermans, Ian F" uniqKey="Hermans I" first="Ian F" last="Hermans">Ian F. Hermans</name>
<name sortKey="Hermans, Ian F" sort="Hermans, Ian F" uniqKey="Hermans I" first="Ian F" last="Hermans">Ian F. Hermans</name>
<name sortKey="Mester, Brigitta" sort="Mester, Brigitta" uniqKey="Mester B" first="Brigitta" last="Mester">Brigitta Mester</name>
<name sortKey="Ostapowicz, Tess" sort="Ostapowicz, Tess" uniqKey="Ostapowicz T" first="Tess" last="Ostapowicz">Tess Ostapowicz</name>
<name sortKey="Ostapowicz, Tess" sort="Ostapowicz, Tess" uniqKey="Ostapowicz T" first="Tess" last="Ostapowicz">Tess Ostapowicz</name>
<name sortKey="Perera, Travis" sort="Perera, Travis" uniqKey="Perera T" first="Travis" last="Perera">Travis Perera</name>
<name sortKey="Weinkove, Robert" sort="Weinkove, Robert" uniqKey="Weinkove R" first="Robert" last="Weinkove">Robert Weinkove</name>
<name sortKey="Weinkove, Robert" sort="Weinkove, Robert" uniqKey="Weinkove R" first="Robert" last="Weinkove">Robert Weinkove</name>
</country>
<country name="République populaire de Chine">
<noRegion>
<name sortKey="Li, Peng" sort="Li, Peng" uniqKey="Li P" first="Peng" last="Li">Peng Li</name>
</noRegion>
</country>
<country name="Australie">
<noRegion>
<name sortKey="Ritchie, David" sort="Ritchie, David" uniqKey="Ritchie D" first="David" last="Ritchie">David Ritchie</name>
</noRegion>
</country>
<country name="États-Unis">
<noRegion>
<name sortKey="Bollard, Catherine M" sort="Bollard, Catherine M" uniqKey="Bollard C" first="Catherine M" last="Bollard">Catherine M. Bollard</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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