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)
| Autor: | Nathaniel Dasyam, Tess Ostapowicz, Chris Frampton, Robert Weinkove, Giulia Giunti, Evelyn Bauer, Bethany Andrews, David Ritchie, Catherine M. Bollard, Peng Li, Travis Perera, Ian F. Hermans, Philip George, Brigitta Mester |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Oncology
Adult Male medicine.medical_specialty Lymphoma B-Cell Adolescent T-Lymphocytes Follicular lymphoma non-hodgkin lymphoma Immunotherapy Adoptive Young Adult CD28 Antigens Internal medicine medicine Protocol Humans B-cell lymphoma Aged Receptors Chimeric Antigen Clinical Trials Phase I as Topic chimeric antigen receptor business.industry General Medicine Middle Aged medicine.disease Chimeric antigen receptor Toll-Like Receptor 2 Lymphoma Fludarabine Transplantation clinical trial protocol Cytokine release syndrome Mantle cell lymphoma Female Neoplasm Recurrence Local business medicine.drug New Zealand Haematology (Incl Blood Transfusion) CD19 Antigen B-Cell Lymphoma |
| Zdroj: | BMJ Open |
| ISSN: | 2044-6055 |
| Popis: | IntroductionAutologous 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 analysisEligible 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 disseminationEthical 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 numberNCT04049513 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|