Yale Team Identifies Targets for Boosting CAR-T Cell Therapy

Researchers at Yale have described a method to “supercharge” T cells against cancer, findings that could improve the effectiveness of a specific type of cancer immunotherapy and expand the cancers it can be used to treat.

Researchers in the lab of Sidi Chen, associate professor of genetics at Yale and senior author of the paper, first developed a way to efficiently scan the genome of CD8 T cells for specific genes that might enhance the cells’ ability to attack cancer cells. “We developed a new kind of genome-wide gain of function screen to find a molecular enzyme that acts like a foot on a gas pedal to increase metabolic activity in T cells,” Chen said.

They found that high levels of activity in several genes—including PRODH2, a gene involved in cell metabolism—stimulate increased Chimeric antigen receptor (CAR)-T cell activity in mouse models of three different types of cancers, including solid-tumor breast cancer.

“Targeted knockin or overexpression of a lead target, PRODH2, enhanced CAR-T-based killing and in vivo efficacy in multiple cancer models,” according to the paper, published recently in Cell Metabolism. “Transcriptomics and metabolomics in CAR-T cells revealed that augmenting PRODH2 expression reshaped broad and distinct gene expression and metabolic programs.”

The discovery can advance CAR-T cell therapy, which harnesses the immune response of T cells to cancers by introducing tumor-detecting molecules into the cells. In the last decade, the U.S. Food and Drug Administration has approved six CAR-T cell therapies to treat B cell lymphomas and multiple myeloma. But despite early successes, the effectiveness of the treatment tends to diminish over time, leading to a search for ways to boost function of T cells.

There are also currently no approved CAR-T cell therapies to treat solid tumors.

Future studies can test the newly identified types of metabolically enhanced CAR-Ts in clinical settings to identify other T cell super-chargers and extend cell-based immunotherapy to different cancer types, especially solid tumors, Chen said.