| Title: |
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) |
| Authors: |
George, Philip; Dasyam, Nathaniel; Giunti, Giulia; Mester, Brigitta; Bauer, Evelyn; Andrews, Bethany; Perera, Travis; Ostapowicz, Tess; Frampton, Chris; Li, Peng; Ritchie, David; Bollard, Catherine M; Hermans, Ian F; Weinkove, Robert |
| Publisher Information: |
BMJ Publishing Group Ltd |
| Publication Year: |
2020 |
| Collection: |
HighWire Press (Stanford University) |
| Subject Terms: |
Protocol |
| Description: |
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 ... |
| Document Type: |
text |
| File Description: |
text/html |
| Language: |
English |
| Relation: |
http://bmjopen.bmj.com/cgi/content/short/10/2/e034629; http://dx.doi.org/10.1136/bmjopen-2019-034629 |
| DOI: |
10.1136/bmjopen-2019-034629 |
| Availability: |
http://bmjopen.bmj.com/cgi/content/short/10/2/e034629; https://doi.org/10.1136/bmjopen-2019-034629 |
| Rights: |
Copyright (C) 2020, British Medical Journal Publishing Group |
| Accession Number: |
edsbas.3080B749 |
| Database: |
BASE |