The p53 protein plays a significant role in cell biology as it regulates the cell cycle and halts the formation of tumors. Scientists have long dubbed the protein p53 as the “guardian of the genome,” because of its role in maintaining DNA integrity. Cells without working p53 are unable to properly repair damaged DNA, leading to a buildup of mutations. Now, researchers at the University of Pennsylvania report a variant of the p53 protein may play an important role in improving the effectiveness of chimeric antigen receptor (CAR) T cell therapy.

The findings are published in The Proceedings of the National Academy of Sciences in an article titled, “Enhancing chimeric antigen receptor T cell therapy by modulating the p53 signaling network with Δ133p53α,” 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 researchers believe their findings point to the importance of the p53 signaling network as a regulator of prolonged CAR T cell responses and could inform the development of improved therapies that harness cancer-fighting T cells.

“In summary, our findings point to the potential for using the p53 isoform Δ133p53α to improve CAR T cell antitumor function through the modulation of the p53 signaling network. Constitutive expression of Δ133p53α may represent a viable translational strategy for improving CAR T cell therapy in CLL and in solid tumor indication and warrants further investigation,” concluded the researchers.

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