Fine-tuning CAR T cell therapy to reduce side effects

Australian and Israeli researchers have developed a way to potentially reduce the toxic side effects of a new type of immunotherapy, in findings that could overcome the pioneering treatment’s biggest limitation.

CAR T cell therapy 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 remission in some patients — even after a patient has stopped taking cancer medication — but a significant limitation is the treatment’s harmful side effects, with about 50% of patients experiencing complications including fever, high blood pressure and respiratory distress. For this reason, the treatment is currently used as a last resort.

A new study, led by the Walter and Eliza Hall Institute of Medical Research (WEHI) and the Weizmann Institute of Science, has now designed a way to identify a ‘goldilocks’ window that strikes a balance of safety and efficacy. The team’s approach, published in the journal eLife, fine-tunes the cells used in the immunotherapy so that their activity is strong enough to eliminate the cancer but not so strong that they generate toxic side effects.

CAR T cell therapies involve collecting T cells from a cancer patient and supercharging the cells by individually re-engineering them in the laboratory. These enhanced cells are then put back into patients.

The T cells are engineered to produce proteins on their surface called chimeric antigen receptors (CARs), which act as artificial sensors that enable T cells to recognise and bind to specific proteins on the surface of cancer cells more efficiently. WEHI Associate Professor Matthew Call said this synthetic sensor is what gives T cells the enhanced ability to attack and eliminate threats like cancer cells.

“While putting these supercharged T cells into a patient with a high tumour burden can swiftly eradicate cancer cells, it also creates the perfect storm for an ongoing toxic response that can be harmful,” Call said. Furthermore, there is currently no way of reliably predicting how strong CAR T cell therapy will be for a patient.

While previous studies have attempted to fine-tune T cells by targeting the end sections of the sensor, which either bind to the cancer cell or instruct the T cells to kill, the new research was focused on completely redesigning the middle part. Researchers leveraged the computational expertise of the Weizmann Institute of Science to stitch together pieces of natural immune sensors with custom-designed synthetic elements, to generate new circuits that could be used to tune and assess variations of potency.

“Focusing on the connector fragment in the middle allows us to generate different versions of CARs that we know are stronger or weaker, enabling us to customise them to a patient’s potency requirements,” Call said.

“Being able to predictably tune this T cell activity significantly broadens our research, contrary to previous studies, because we are targeting something that exists in every immunotherapy scenario.

“For the first time, we can establish rules that will be applicable to any cancer where CAR T cell immunotherapy is being used.”

WEHI Associate Professor Melissa Call said the ability to fine-tune T cells would dramatically reduce the number of patients experiencing severe side effects from the treatment. “This would allow patients with a broad range of cancers to be given CAR T cell therapy far earlier in the treatment process,” she said.

The researchers hope their new tool could be used to triage immunotherapy patients based on the level of potency they require in early phases of their treatment and bring the field closer to striking that goldilocks treatment window for many different cancers. The next research phase will focus on progressing their findings into a clinical setting to see CAR T cell therapy used as a safer, first-line treatment.

Image credit: ©stock.adobe.com/au/Andrea Danti

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