CAR T cell immunotherapy, illustration

Researchers at the Medical University of Vienna have identified “exhausted” T cells in lymphoma patients as a potent biomarker that can be used to predict the success of CAR-T cell therapy in patients.

In recent years, CAR-T cell therapy has been approved for lymphoma patients. CAR-T cells are lymphocytes taken from an individual patient and genetically engineered to express proteins known as CAR—chimeric antigen receptors—on their surface in order to bind specific proteins on the surface of cancer cells and eliminate them. Despite its relative effectiveness, this therapy does not work for all patients.

Reporting in Frontiers in Immunology, researchers at the Medical University of Vienna have identified a possible reason for CAR-T cell therapy failure. In their study, the scientists discovered that many lymphoma patients suffer from T lymphocyte deficiency, often accompanied by “exhausted” T cells—cells that have lost their ability to kill cancer cells.

“Our study shows how important the nature of the T cells is for CAR-T cell production and that exhausted T cells, which can be found in a considerable proportion of patients, pose a problem for subsequent CAR-T cell therapy,” said Winfried Pickl, PhD, professor of immunology at the Medical University of Vienna and senior author of the study.

The researchers found that significantly increased numbers of “exhausted” T cells in lymphoma patients led to a low probability of responding to CAR-T cell therapy. This is because the patient’s own T cells are used as starting material for CAR-T cell production. According to the researchers, “exhausted” T cells may not be able to persist in patients for longer periods of time, limiting their long-term efficacy.

Markers that have previously been used to predict responsiveness to CAR-T cell therapy include low lactate dehydrogenase (LDH) levels after removing all lymphocytes from the patient and before the infusion of CAR-T cells. However, LDH levels are not directly related to the immune system, making them less reliable for prediction.

“The low frequency of exhausted … T cells at the time of leukapheresis represents a new blood biomarker that can be used even before the start of CAR-T cell production and infusion and predicts the response to treatment with CAR-T cells in patients. Removal of such cells from the leukapheresis product prior to the initiation of CAR-T cell production could significantly improve the success of therapy even in patients with an unfavorable initial situation,” Pickl concluded.

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