18 December 2023

A trial of a ‘third generation’ anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown good results for relapsed or refractory B-Cell non-Hodgkin’s lymphomas, researchers have reported at the Annual Meeting of the American Society of Hematology (ASH).

Earlier CAR-T cell therapies are widely used for lymphomas, but can cause severe side-effects including neurotoxicity and cytokine release syndrome (CRS). So, Dr Robert Weinkove, from the Malaghan Institute of Medical Research in New Zealand, and colleagues searched for an improvement which “combine high efficacy with low toxicity”.

They investigated the safety and efficacy of a novel CD19-directed therapy in a Phase 1 trial. Their new CAR-T therapy combines CD28 with a toll-like receptor 2 (TLR2) co-stimulatory domain. Previous pre-clinical studies have shown that adding this domain maintains the same efficiency while reducing pro-inflammatory cytokines that cause severe side-effects.

The new CAR-T cell therapy was given to 21 patients with a median age of 57 years. Among the participants, 19% were Māori.

The therapy caused no severe CRS, and notably, no neurotoxicity of any grade. Clinical responses were seen at all dose levels, with a three-month complete response rate of 52%.

Dr Weinkove said: “The absence of neurotoxicity with a CD28-based anti-CD19 CAR T-cell therapy is remarkable. Adding the intracellular TLR2 domain with CD28 and CD3-zeta alters the CAR T-cell cytokine profile and may account for our clinical findings.

“We are enrolling to a dose expansion cohort, with outpatient management and automated manufacture of WZTL-002 CAR T-cells. This is helping us prepare for a phase 2 trial in early 2024, to assess efficacy and safety in a larger number of patients.”

CAR T-cell therapy developer Professor Carl June, of New Zealand company BioOra Limited, commented: “Dr Weinkove and his team at the Malaghan Institute have shown efficacy that is on par with commercial CAR T, but the safety signal appears superior.”


Weinkove R, George P, Fyfe R, Dasyam N, Nouri Y, Ostapowicz T, Mullins S, Mester B, Giunti G, Bollard CM, Perera R, Jina H, D'Souza A, Qin L, Ritchie DS, Frampton CMA, Perret R, Li P, Hermans I (2023) “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).” Oral presentation at the 65th American Society for Hematology (ASH) Annual Meeting, San Diego.

Link: https://ash.confex.com/ash/2023/webprogram/Paper178872.html

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