Third generation CAR T therapy to lower neurotoxicity in B-cell lymphoma

Chimeric antigen receptor (CAR) T-cell therapies directed against CD19 and incorporating either CD28 or 4-1BB intracellular co-stimulatory domains are a standard of care for relapsed or refractory (r/r) B-cell lymphomas. A phase 2 clinical trial of a new CAR T-cell therapy is getting underway in New Zealand, on the back of promising phase 1 results that suggest improved safety compared with leading commercial CAR T-cell therapies, while remaining highly effective for B-cell non-Hodgkin lymphomas.

Malaghan Institute Clinical Director Dr Robert Weinkove said commencing a phase 2 trial at Wellington Hospital is a major step towards CAR T-cell therapy becoming a standard of care for certain blood cancers in New Zealand.

“We have final regulatory and ethical approvals, our first site is ready to go, and clinicians around New Zealand have been advised of the criteria and how to refer patients. We hope this new trial will confirm effectiveness and safety of our new NZ-developed CAR T-cell therapy and result in registration for routine use in New Zealand and overseas,” Dr Weinkove stated.

“Our CAR T-cell product shares one of its domains with commercial CAR T-cell therapies called axi-cel (Yescarta) and brexu-cel (Tecartus). Axi-cel and brexu-cel are very effective treatments, but neurotoxicity affects up to half of recipients. We think that adding the new TLR2 (Toll-like Receptor 2) domain in our construct has lowered the neurotoxicity rate, hopefully while maintaining effectiveness,” he added. “Apart from the direct benefit to patients, a low neurotoxicity rate means that we can treat patients without routinely admitting them to hospital for monitoring, lowering costs for the health system.”

Within the ENABLE-2 trial, 60 adults with certain types of relapsed or refractory large B-cell non-Hodgkin lymphoma will be treated over two years. After assessing the dose and safety of this new CAR T-cell therapy in a phase 1 trial where patients had exhausted all other treatments, patients will be treated earlier in their treatment pathway for ENABLE-2.

“We are hopeful that treating patients earlier – as a second- or third-line therapy – will result in even better CAR T-cell outcomes as their immune system function may have been less damaged by their prior cancer treatments. This may also limit the need for patients to go through repeated chemotherapies with diminishing returns,” commented Dr Weinkove.

“The safety profile of our new CAR T-cell therapy also means we can deliver it as an outpatient treatment, lowering the burden on patients and their whānau, and reducing costs to the health system.”

The Malaghan Institute started New Zealand’s first trial of CAR T-cell therapy in late 2019, in collaboration with Wellington Zhaotai Therapies Limited, to assess the safety of a new ‘third generation’ CAR T-cell therapy and develop and support the regulatory and clinical environment for safe CAR T-cell delivery in New Zealand.

“We hope this new trial will confirm effectiveness and safety of our new NZ-developed CAR T-cell therapy and result in registration for routine use in New Zealand and overseas.”

In the ENABLE phase 1 trial, 30 New Zealanders were treated with the new CAR T-cell therapy, with results showing no limiting toxicities and more than half the patients in complete response three months after treatment.

ENABLE also established automated manufacture and delivery of CAR T-cells by BioOra Limited, a New Zealand start-up incubated at the Malaghan Institute and established with Bridgewest Ventures in 2021 to optimise and scale-up CAR T-cell manufacturing in New Zealand.

“Automation offers efficiencies and scalability that will lower barriers to this ground-breaking treatment,” said BioOra Managing Director John Robson. “Our unique automated process for this personalised therapy will enable us to manufacture CAR T-cells more consistently at lower cost, and to treat more patients – for this trial and beyond.”

Dr Weinkove said the Malaghan Institute and BioOra are in active discussions with government and health sector colleagues about next steps, while putting in place the manufacturing, distribution and health service integration measures that could establish this therapy as a standard of care if the phase 2 trial is successful.

“A number of CAR T-cell therapies have been registered based on phase 2 trials. One of the key objectives of the phase 2 trial is to support registration of our CAR T-cell therapy in New Zealand and Australia. We would like to maximise the chances of timely uptake within the public health system to limit gaps in treatment availability for those who need it,” said Dr Weinkove.

“As a charity, the Malaghan Institute is hugely grateful to and reliant on our funders and donors for helping us bring this ground-breaking therapy to New Zealand, and demonstrate a new way to bring innovative, affordable new treatments into the New Zealand healthcare system.”

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