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)

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.

Keywords: B-Cell Lymphoma; CD19 Antigen; chimeric antigen receptor; clinical trial protocol; non-hodgkin lymphoma.

Figure 1

Diagrammatic representation of WZTL-002 anti-CD19 third-generation chimeric antigen receptor (CAR) T-cell illustrating the costimulatory domains and components of the CAR.

Figure 2

Schema for the enable phase I dose escalation study. Second attempt at cell harvest and WZTL-002 production may be considered at discretion of TMC. Six-month PET scan if first PET scan post WZTL-002 treatment shows partial response. Long-term follow-up through bone marrow transplant clinic and Cellular Therapies Registry enrolment. FluCy, fludarabine and cyclophosphamide IV; PET, positron emission tomography; TMC, trial management committee.