by Malaghan Institute of Medical Research

Malaghan Institute GMP lab where CAR T-cells were manufactured for the phase 1 trial. Credit: Malaghan Institute of Medical Research

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. The research is also published in the journal Blood.

Anti-CD19 CAR T-cells with a CD28 co-stimulatory domain, such as axicabtagene ciloleucel and brexucabtagene autoleucel, are among the most effective CAR T-cell therapies for B-cell non-Hodgkin lymphomas but are associated with neurotoxicity (immune effector cell-associated neurotoxicity syndrome, ICANS) in around half of recipients, and cytokine release syndrome (CRS) in up to 90%.

The Malaghan Institute and Wellington Zhaotai Therapies Limited have developed a third generation autologous anti-CD19 CAR T-cell product, which combines CD28 with a toll-like receptor 2 (TLR2) co-stimulatory domain. In preclinical studies, adding the TLR2 domain maintained or improved efficacy, while lowering production of the pro-inflammatory cytokines IFN-γ and GM-CSF, which are implicated in CRS and ICANS, compared to a CAR with CD28 co-stimulation alone.

This is what ground-breaking CAR T-cell therapy looks like. Credit: Malaghan Institute of Medical Research

Twenty-one patients with relapsed or refractory B-cell non-Hodgkin lymphomas were treated in the dose escalation cohort of a phase 1 trial and completed the primary follow-up period. Median age was 57 years, 19% were Māori, participants had received a median of four prior lines of therapy.

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. A phase 2 dose range of 5 × 10⁵ to 1 × 10⁶ cells/kg was recommended. A further four patients have since been treated at this dose within a dose expansion cohort and have reached the DLT assessment timepoint; among these four additional patients, no grade ≥ 3 CRS or ICANS of any grade occurred.

"The absence of neurotoxicity with a CD28-based anti-CD19 CAR T-cell therapy is remarkable. Adding the intracellular TLR2 domain with CD28 and CD3ζ alters the CAR T-cell cytokine profile, and may account for our clinical findings," says Malaghan Institute Clinical Director and Principal Investigator Dr. Robert Weinkove.

"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-cells in action. Pink CAR T-cells, manufactured at the Malaghan Institute, are shown attacking a clump of green blood cancer cells. As the cancer cells die they turn blue. Credit: Malaghan Institute of Medical Research

The original TLR2-containing CAR T constructs were developed at the Guangzhou Institute of Biomedicine and Health in China in collaboration with the Hunan Zhaotai Medical Group. In 2017, Wellington Zhaotai Therapies Limited was formed as a joint venture between the Malaghan Institute and Hunan Zhaotai Medical Group to develop this technology for international markets. The clinical trial of autologous anti-CD19 CAR T-cell therapy combining CD28 and TLR2 costimulation, WZTL-002, commenced in 2019. In 2023, Wellington Zhaotai Therapies Limited entered into a license agreement with Dr. Reddy's Laboratories to develop a CAR T-cell therapy incorporating this construct.

"These results are another exciting milestone in the development of our novel CAR T technology and the future of CAR T therapies globally," says Peter Lai, Wellington Zhaotai Therapies Limited Executive Director.

More information: Robert Weinkove et al, 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), Blood (2023). DOI: 10.1182/blood-2023-178872

Provided by Malaghan Institute of Medical Research