WZTL-002 / Wellington Zhaotai Therapies - LARVOL DELTA

A Phase 1 Dose Escalation Trial of Third-Generation CD19-Directed CAR T-Cells Incorporating CD28 and Toll-like Receptor 2 (TLR2) Intracellular Domains for Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas (ENABLE) (ASH 2023) - P1 | "WZTL-002 CAR T-cells were administered intravenously after 3 days of fludarabine (30mg/m2/day) and cyclophosphamide (500mg/m2/day) lymphodepletion...Grade 1 – 2 CRS occurred in 13 patients (62%); 6 received tocilizumab and 3 dexamethasone... In this dose escalation trial of a novel third-generation CD19-directed CAR T-cell product that combines CD28 and TLR2 co-stimulatory domains for r/r B-NHL, we observed no severe CRS, no ICANS of any grade and complete responses at all dose levels. At RP2D, in vivo CAR T-cell expansion was similar to or greater than other CD19-directed products. In conjunction with preclinical findings, this study suggests interposition of a TLR2 domain between CD28 and CD3ζ domains may reduce CAR T-cell-related ICANS risk while retaining efficacy."

CAR T-Cell Therapy • P1 data • Anemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia • CD4 • CD8 • CSF2 • IFNG • IL7 • TLR2

A Phase 1 Dose Escalation and Expansion Trial of Third-Generation CD19-Directed CAR T-Cells Incorporating CD28 and Toll-like Receptor 2 (TLR2) Co-Stimulation for Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas (ENABLE-1) (ASH 2024) - P1, P2 | "Bridging therapy was permitted between leukapheresis and lymphodepletion (fludarabine 30mg/m2/day & cyclophosphamide 500mg/m2/day ×3d); WZTL-002 CAR T-cells were given intravenously 2d later...Grade 1 or 2 CRS occurred in 17 patients (57%) no grade ≥3 CRS events occurred; 9 (30%) received tocilizumab and 3 (10%) dexamethasone for CRS...This safety profile could facilitate outpatient management, lower treatment costs and improve the patient experience of CAR T-cell therapy. A phase 2 trial of WZTL-002 as 2nd or 3rd line treatment for r/r LBCL has commenced (ENABLE-2, NCT06486051)."

CAR T-Cell Therapy • P1 data • Anemia • B Cell Non-Hodgkin Lymphoma • CNS Disorders • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia • CD4 • CD8 • CSF2 • IFNG • TLR2

A phase 2 trial to evaluate the efficacy and safety of WZTL-002, a third-generation anti-CD19 CAR T-cell therapy, in patients with relapsed or refractory large B-cell lymphoma (ENABLE-2). (ASCO 2025) - P1, P2 | "Lymphodepletion comprises intravenous fludarabine (30mg/m2) and cyclophosphamide (500mg/m2) daily for 3 days. Secondary outcomes include safety (with CRS, ICANS and cytopenias as adverse events of special interest), and progression-free, event-free and overall survival. The first participant was enrolled on 13 August 2024."

CAR T-Cell Therapy • Clinical • P2 data • B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • TLR2

WZTL-002 CAR T Cells Show Potential in Treatment of Relapsed or Refractory B-Cell NHL (Blood Cancers Today) - P1 | N=30 | ENABLE-1 (NCT04049513) | "WZTL-002 yielded a CR rate of 52% in the 21-patient dose escalation cohort and 56% in the 6-patient dose expansion cohort. Of those treated at the recommended phase 2 dose, the WZTL-002 had a geometric mean mean CAR T-cell level of 29,515 transgenes/μg genomic DNA, and CARs remained detectable at day 90 in 14 patients (88%)...Regarding CRS, grade 1/2 events occurred in 17 patients (57%), and no events of grade 3 or higher were observed. Of the patients who had CRS, nine (30%) received tocilizumab and three (10%) received dexamethasone as treatment. No patients in the study needed intensive care within 28 days of receiving WZTL-002."

P1 data • B Cell Non-Hodgkin Lymphoma

ENABLE-2: A Study of WZTL-002 CAR T-cells for Adults With Relapsed Large B-cell Lymphoma (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Malaghan Institute of Medical Research | Not yet recruiting ➔ Recruiting

CAR T-Cell Therapy • Enrollment open • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

ENABLE-2: A Study of WZTL-002 CAR T-cells for Adults With Relapsed Large B-cell Lymphoma (clinicaltrials.gov) - P2 | N=60 | Not yet recruiting | Sponsor: Malaghan Institute of Medical Research

CAR T-Cell Therapy • New P2 trial • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

ENABLE (Engaging Toll-like Receptor Signalling for B-cell Lymphoma Chimeric Antigen Receptor Therapy) (clinicaltrials.gov) - P1 | N=30 | Active, not recruiting | Sponsor: Malaghan Institute of Medical Research | Recruiting ➔ Active, not recruiting

CAR T-Cell Therapy • Enrollment closed • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Mantle Cell Lymphoma • Mediastinal B Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19

Third-generation anti-CD19 CAR T-cells demonstrate efficacy without neurotoxicity in B-cell lymphoma phase 1 clinical trial (Eurekalert) - P1 | N=30 | ENABLE (NCT04049513) | "The Malaghan Institute of Medical Research in collaboration with Wellington Zhaotai Therapies Limited today announced results of its phase 1 dose escalation trial of a new third generation anti-CD19 chimeric antigen receptor (CAR) T-cell therapy to be presented at the American Society of Hematology (ASH) Annual Meeting in San Diego on 11 December, 3pm....No dose limiting toxicities occurred at doses of 5 × 104 to 1 × 106 CAR T-cells/kg. Grade 1 or 2 CRS occurred in 13 patients (62%); no severe (grade ≥ 3) CRS occurred. Notably, no ICANS of any grade occurred. Clinical responses were seen at all dose levels, with a 3-month complete response rate of 52%. WZTL-002 CAR T-cell expansion was robust."

P1 data • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Trial results offer hope to Kiwis with incurable blood cancer (Malaghan Institute of Medical Research) - P1 | N=30 | ENABLE (NCT04049513) | "The Malaghan Institute’s ENABLE phase 1 safety trial began in late 2019, in partnership with Wellington Zhaotai Therapies Ltd, treating 21 New Zealanders with relapsed or refractory B-cell non-Hodgkin lymphoma who had exhausted all conventional treatment options...The trial found no limiting toxicities at any of the doses tested. Importantly, none of the participants developed neurotoxicity or severe cytokine release syndrome – common side effects of some commercial CAR T-cell therapies. The trial also showed promising effectiveness, with around half of the participants’ lymphomas in complete response three months after receiving the treatment....'We are already treating patients in an ‘expansion cohort’, for which we have automated the CAR T-cell manufacturing process with our partners at BioOra, and we are giving the CAR T-cells as an outpatient therapy.'"

P1 data • Trial status • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

ENABLE (Engaging Toll-like Receptor Signalling for B-cell Lymphoma Chimeric Antigen Receptor Therapy) (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Malaghan Institute of Medical Research | N=12 ➔ 30 | Trial completion date: Aug 2026 ➔ Feb 2029 | Trial primary completion date: Sep 2021 ➔ May 2024

CAR T-Cell Therapy • Enrollment change • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Mantle Cell Lymphoma • Mediastinal B Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19

A phase 1 trial of TLR2-costimulated third-generation anti-CD19 CAR T-cells for relapsed/refractory B non-Hodgkin lymphomas (BSH 2023) - P1 | "Registry data indicate a CD28-costimulated anti-CD19 CAR T-cell product (axi-cel, 1928z) results in higher response rates, but more frequent neurotoxicity and severe cytokine release syndrome (CRS), than a 41BB-costimulated product (tisa-cel, 19BBz)...Following fludarabine and cyclophosphamide lymphodepletion, 5 × 10e4/kg to 1 × 10e6/kg autologous 1928T2z CAR T-cells were administered to 20 patients with relapsed or refractory B-cell non-Hodgkin lymphomas...Preliminary phase 1 clinical trial findings suggest third-generation 1928T2z CAR T-cells combine a low incidence of severe CRS and neurotoxicity with encouraging efficacy and robust expansion at low dose. Clinical investigation of 1928T2z CAR T-cells is ongoing."

CAR T-Cell Therapy • P1 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Immune Modulation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CSF2 • IFNG • IL7 • MYD88 • TLR2

Next-Generation 1928T2Z CAR T Cells Best Current-Generation Constructs (Targeted Oncology) - P1 | N=12 | ENABLE (NCT04049513) | "Nouri showed that 1928T2Z CAR T cells have equivalent or better cytotoxicity compared with 1928z in the ENABLE phase 1 dose escalation trial...Cytotoxicity was measured using an Incucyte assay, which found that TLR2 signaling contributed to the activation and cytotoxicity of 1928T2Z CAR T cells....In preliminary data from ENABLE, Nouri said that at all dose levels, which range from 5 × 104 cells/kg up to 1 × 106, no cases of grade 3 and higher CRS and no cases of ICANS have been observed."

P1 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology

ENABLE: A phase 1 trial of third-generation CAR T cells for relapsed/refractory B-cell lymphomas—an out of program clinical research fellowship experience (BSH 2022) - P1 | "A single dose of WZTL-002 is administered following cyclophosphamide and fludarabine conditioning. The process of setting up this trial as part of a Clinical Research Fellowship on an 'Out of Program Research Placement' from a UK Haematology Registrar Training program, will be outlined. The potential future direction of this treatment modality within New Zealand will be discussed."

CAR T-Cell Therapy • Clinical • P1 data • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Third-generation CAR T-cells incorporating a TLR2 co-stimulatory domain combine enhanced cytotoxicity with reduced inflammatory cytokine production: Pre-clinical and phase 1 clinical trial findings (EHA-EBMT-CART 2023) - P1 | "Registry data suggest a CD28-costimulated anti-CD19 CAR T-cell product (axi-cel, 1928z) results in higher response rates, but increased neurotoxicity and severe cytokine release syndrome (CRS), than a 41BB-costimulated product (tisa-cel, 19BBz)...In an ongoing phase 1 dose-escalation trial, we administered fludarabine and cyclophosphamide lymphodepletion followed by 5 × 104/kg to 1 × 106/kg 1928T2z CAR T-cells to 19 patients with relapsed or refractory B-cell non-Hodgkin lymphomas...* = P<0.05, ** = P<0.01, *** = P<0.001, **** = P<0.0001.ParticipantLymphoma subtypeDose(1928T2z CAR T-cells/kg)CRS(highest grade)ICANS(highest grade)3 month responseEN1-01EN1-02EN1-03EN1-04EN1-05EN1-07EN1-12EN1-13EN1-14EN1-08EN1-15EN1-16EN1-17EN1-18EN1-20EN1-21EN1-22EN1-23EN1-24FLMCLDHLFLDLBCLDHLDLBCLDLBCLDLBCLDLBCLtFLPMBCLtFLDLBCLTHRLBCLDLBCLDLBCLFLDLBCL5 × 1045 × 1045 × 1041 × 1051 × 1051 × 1052 × 1052 × 1052 × 1055..."

CAR T-Cell Therapy • IO biomarker • P1 data • Preclinical • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Immune Modulation • Inflammation • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Histiocyte Rich Large B Cell Lymphoma • CSF2 • IFNG • IL7 • TLR2