CAR T-cell immunotherapies for cancer

CAR T-cell therapy is a new form of immunotherapy that enhances a patient’s killer immune cells to attack and eliminate cancer.

It can be up to 90% effective in certain blood cancers and can even deliver long-term remissions and cures in some patients. But a significant limitation is the treatment’s harmful side-effects, with about 50% of patients experiencing dangerous complications.

A new study, led jointly by WEHI researchers in collaboration with Israel’s Weizmann Institute of Science, has designed a new way to identify a ‘goldilocks’ window that strikes a balance of safety and efficacy.

The team’s approach fine-tunes the cells used in the immunotherapy, to ensure that their activity is strong enough to eliminate the cancer, but not so strong that they generate toxic side effects. This will significantly enhance patients' quality of life and wellbeing before, during, and after treatment.

Additionally, improving safety will have beneficial effects on healthcare costs and equitable access.

Since the first engineered immune receptors (CARs) were tested nearly three decades ago with cancer immunotherapy in mind, the design process has been largely trial and error – few fundamental principles have been established to ensure CAR designs yield predictable T-cell responses. The computationally designed CAR ‘parts’ control the molecular groupings of receptors in CAR T-cells, providing a completely new way to predictably tune CAR T-cell therapies to elicit stronger or weaker immune responses to tumours. This approach, is referred to as ‘programmed’ CAR T-cells, or proCAR T-cells, and has significant clinical potential because it will help to precisely balance the safety and efficacy of CAR T-cell therapies for different cancers.

This is a crucial and delicate balance because immune responses that are too strong and toxic are potentially lethal for patients receiving treatments, while those that are too weak are simply ineffective against the cancer.

With HM1 support, WEHI researchers are developing proCAR T-cells for blood and brain cancers, collaborating with other scientists and clinicians at WEHI, the Peter MacCallum Cancer Centre (Melbourne) and the Weizmann Institute of Science (Tel Aviv, Israel). The advances have also led to new collaborations in additional areas such as cell-based cancer vaccines (WEHI) and autoimmune diabetes (Monash University).

A better future

There are currently over 600 clinical trials of CAR T-cell immunotherapy, with the treatment already being used for several blood cancers.

HM1 funding has supported the development of two preclinical workflows designed to test WEHI’s proCAR T-cells in two cancer contexts, where the safety/efficacy balance is particularly critical and has been limiting in practice. For brain cancers, local strong inflammation due to cytokines can cause severe neurological damage. Whereas in blood cancers, the high burden of disseminated tumour cells commonly leads to CAR T-cell-induced systemic cytokine release syndrome (CRS), a dangerous condition similar to bacterial sepsis or severe COVID-19 infection.

WEHI now has data showing that two of the new human proCAR T-cell formulations can reduce cytokine production and mitigate off-target activity compared to the original design of a proprietary WEHI CAR T-cell therapy for glioblastoma. Importantly, these retain their strong ability to kill the target tumour cells in the lab, and the first of these is now being tested for efficacy in a preclinical model of human brain cancer in collaborator A/Prof Misty Jenkins’ lab (WEHI).

WEHI has also developed eight new human proCAR T-cell products for a subset of blood cancers (B-ALL, DLBCL, follicular lymphoma, and possibly mantel cell lymphoma) that they believe will provide high efficacy with lower toxicity than their FDA-approved counterparts. Half of these have been tested in the lab and are currently being prepared for safety and efficacy studies in pre-clinical models of human blood cancers; the other half are still in the lab-based testing phase. When these blood cancer experiments are finished, the data will be analysed with clinical collaborator A/Prof Michael Dickinson (Peter Mac) to determine their potential for clinical trials.

The researchers envision significant health impacts will come from this work in the form of improved cancer treatments and increased survival rates for a range of cancers. Their technology is designed to be applicable to most CAR T-cell therapies that are already in use or in clinical trials.

They also hope the improvement in safety and efficacy balance will contribute to simplifying the decision-making process for front-line treatment in appropriate cancer cases. As a result, a multitude of cancer patients, including those with a terminal prognosis, will have the opportunity to receive this transformative treatment during the early stages of their disease.

Spotlight on WEHI’s Young Talent

HM1 funding has also supported the salary and research costs for an outstanding female early-career researcher in the Call Laboratory - cancer immunologist Dr Ashleigh Davey. Dr Davey, having just welcomed her first child in mid-2022, is at the life stage when attrition of female research scientists begins in earnest. The security provided by this funding strengthened her case for promotion to Senior Postdoctoral Research Scientist in 2023, a significant academic step, and it has given WEHI the freedom to plan for her longer-term career development.

WEHI has also leveraged the significant scientific advances to secure an additional $3.5M in competitive grant funding for its broader CAR T-cell therapy program. Dr Davey is a Chief Investigator on several of these grants, which contributes substantially to building her research profile towards being able to establish her own independent research group.