Third-generation anti-CD19 CAR T-cells

…demonstrate efficacy without neurotoxicity in B-cell lymphoma phase 1 clinical trial.

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.

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.

Twenty-one patients with relapsed or refractory B-cell non-Hodgkin lymphomas were treated in the dose escalation cohort of a phase 1 trial (ENABLE, ClinicalTrials.gov NCT04049513) 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.

Deconstructing a CAR T-cell – what’s unique about our CAR T-cell construct? Credit: Malaghan Institute of Medical Research

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.”

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.

“There is a huge need and opportunity to extend CAR T-cell therapies into markets not yet addressed by major pharmaceutical companies. The reduced side effect profile of WZTL-002 creates a promising opportunity to address this unmet need.”

One of the objectives of the dose expansion cohort study is to move CAR T-cell manufacture onto an automated platform, in partnership with New Zealand company BioOra Limited. Professor Carl June, BioOra board member and CAR T-cell therapy pioneer, says the ENABLE trial’s phase 1 CAR T data are a step forward for the treatment of CD19-expressing lymphomas.

“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. This lays the foundation for outpatient delivery and management and expanding indications for their CAR T programme.”

Background

Abstract 890 – 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)

The ENABLE trial was funded by New Zealand’s Ministry of Business, Innovation and Employment, the Thompson Family Foundation, and by private donors, with additional support from Leukaemia & Blood Cancer New Zealand and Life Blood. The Malaghan Institute’s CAR T-cell research programme has been supported by Freemasons NZ and the Health Research Council of New Zealand. Dr Weinkove received a Clinical Practitioners Research Fellowship from the Health Research Council.

About the Malaghan Institute of Medical Research

The Malaghan Institute of Medical Research is an independent biomedical research charity based in Wellington, New Zealand, with a focus on breakthrough discoveries in immunology and immunotherapy. Its key areas of research and discovery include cancer, infectious disease and allergic and inflammatory diseases. www.malaghan.org.nz

About Wellington Zhaotai Therapies Limited

Wellington Zhaotai Therapies Limited is a joint venture company between Hunan Zhaotai Medical Group (Changsha, China) and the Malaghan Institute of Medical Research (Wellington, New Zealand). Established in 2017 to take Hunan Zhaotai’s novel CAR T-cell technology to the global market, the joint venture brings together the best of CAR T-cell research and development in China and New Zealand. www.wellingtonzhaotai.com

About BioOra Limited

Based in New Zealand, BioOra is a privately held biopharma joint venture between the Malaghan Institute of Medical Research and Bridgewest Ventures. It is commercialising CAR-T cell therapy by automating manufacture to introduce efficiency, scalability, and cost savings. This will facilitate access to these life-saving treatments in New Zealand and beyond. As a follow on to the ENABLE trial, BioOra is partnering with the Malaghan Institute to further develop WZTL-002 for patients with lymphoma in New Zealand and Australia. www.bioora.com

Journal: Blood
DOI: 10.1182/blood-2023-178872
Method of Research: Experimental study
Subject of Research: People
Article Title: 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)
Article Publication Date: 2-Nov-2023

Media Contact

Gail Marshall
Malaghan Institute of Medical Research
gmarshall@malaghan.org.nz
Cell: 21360432

www.malaghan.org.nz