Next Generation CAR T Cell Therapy Includes Cancer Suppressor

Researchers at the University of Pennsylvania report a variant of the p53 protein may improve the effectiveness of chimeric antigen receptor (CAR) T cell therapy.

The findings are published in The Proceedings of the National Academy of Sciences and led by Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the department of pathology and laboratory medicine, director of the center for cellular immunotherapies at the Perelman School of Medicine, and director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania.

“CAR T cell therapy, a transformative treatment for blood cancers, is limited by T cell dysfunction, especially in chronic lymphocytic leukemia (CLL),” the researchers wrote. “Our study reveals a pivotal role for the human and great ape-specific p53 isoform, Δ133p53α, in enhancing the therapeutic efficacy of CAR T cells. Expressing Δ133p53α in CAR T cells improves their metabolic robustness, enabling superior antitumor function particularly under high tumor burden conditions.”

June and colleagues targeted the p53 protein variant Δ133p53α, which decreases in expression with age in human T cells.

Continual expression of Δ133p53α improved the antitumor function of CAR T cells manufactured from both healthy normal donors and from people with CLL who failed to respond to CAR T cell therapy during clinical trials. Expressing Δ133p53α in CAR T cells enhanced the cells’ metabolic function, boosting antitumor activity, especially under conditions of high tumor burden. Under nutrient-limiting conditions, CAR T cells expressing Δ133p53α not only cleared significantly more tumor but also displayed increased proliferation, partly due to the enhancement of key biosynthetic processes and improved mitochondrial function.

The findings point to the significant role of the p53 signaling network as a regulator of prolonged CAR T cell responses and provides new avenues of therapies that harness cancer-fighting T cells.