Addressing Exhausted T-Cells in CAR T Therapy: Joseph A. Fraietta, PhD

“The big problem [with autologous CAR T-cells] is, especially in elderly patients who have been heavily pretreated... the quality of those T cells isn't very good... Exhausted T cells really become dysfunctional due to a progressive loss of functionality. They may be exhausted going in, they could become more exhausted during the manufacturing process... [or] they can become exhausted after we infuse them into the patients.”

New research from the Perelman School of Medicine at the University of Pennsylvania may address the problem of exhausted T-cells in chimeric antigen receptor (CAR) T-cell therapy. Investigators, including senior author Joseph A. Fraietta, PhD, assistant professor, microbiology, and director, Solid Tumor Immunotherapy Lab, Center for Advanced Cellular Therapies, University of Pennsylvania, has shown that JQ1, a small-molecule inhibitor currently used to treat a variety of cancers, can “reinvigorate” patient T cells and improve CAR T-cell function.

Fraietta and colleagues found that JQ1 inhibits the bromodomain and extra terminal (BET) proteins, which, in turn, disrupt CAR expression and T cell histone function in chronic lymphocytic leukemia (CLL).

GeneTherapyLive spoke with Fraietta to learn more about the issue of exhausted T-cells in autologous CAR T-cell therapy. He also discussed some of mechanisms of T-cell exhaustion.

REFERENCE

Existing drug may help improve responses to cellular therapies in advanced leukemias. News release. Unviersity of Pennsylvania. August 16, 2021. https://www.pennmedicine.org/news/news-releases/2021/august/existing-drug-may-help-improve-responses-to-cellular-therapies-in-advanced-leukemias