New research into CAR-T cell therapy by researchers at the Walter and Eliza Hall Institute of Medical Research (WEHI) has revealed crucial mechanisms that could help the immunotherapy technique, which is currently only effective against blood cancers, be adapted for the treatment of brain tumors and other forms of solid cancers.

Chimeric Antigen Receptor (CAR) T-cells are synthetically engineered T cells (a type of white blood cell) that are altered to identify and destroy cancer cells. The altered cells are better able to identify specific cancer antigens, which our bodies can have a difficult time recognizing as foreign cells.

In the therapy itself, T cells are removed from the patient's blood via leukapheresis, which can take up to two to three hours to complete, changed and then returned into the patient a few weeks later, once enough CAR-T cells have been created to launch a precise attack. Currently, there are two CAR-T cell therapies approved by the FDA in the United States – one for advanced or recurrent acute lymphoblastic leukemia and the other for large B-cell lymphoma.

These therapies are generally successful in these blood cancers, but have mixed results and can frequently cause severe side effects when treating solid cancers, such as brain tumors. One side effect, cytokine release syndrome (CRS), is a potentially fatal inflammatory response that can lead to high fevers, dangerously low blood pressure and even organ failure in some patients.

Dr Misty Jenkins, with colleagues Mr Alex Davenport, Associate Professor Phillip Darcy and Associate Professor Paul Neeson from the Peter MacCallum Cancer Centre, said the new research showed for the first time how CAR-T cells interacted with cancer cells.

"We found that CAR-T cell receptors have the ability to rapidly identify and bind to tumour cells that would otherwise remain undetected in the immune system, and promptly kill them," Dr Jenkins says. "We have previously shown a correlation between cytokine production and the length of time the immune cells were latched onto the cancer cells. The longer the cells were in contact, the more cytokines were produced, causing ever increasing degrees of damage from inflammation."

Further research into the biological factors that contribute to the efficacy and side effects of CAR-T cell therapy may help in creating a better treatment and safer delivery techniques, so as to reduce the recurrence of CRS. Although brain tumors are often resistant to traditional cancer treatments and surgical removal can be difficult, the team hopes that their new findings will allow CAR-T cell therapy to be adapted for use against brain cancer and other solid tumors.

"Finding an optimum design for CAR-T cell therapy where we can kill tumour cells with limited invasion, inflammation and side effects could significantly improve the treatment of brain cancer," says Dr Jenkins. "Answering fundamental biological questions about how immune cells and cancer cells function and interact, as we have done in this study, is invaluable in the quest to find formidable treatments for fatal cancers."

The study can be found in the journal Proceedings of the National Academy of Sciences.

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