Innovative Protein Engineering Enhances CAR-T Cell Effectiveness Against Diverse Cancers

Researchers at Yale University have developed a cutting-edge protein engineering toolset aimed at significantly improving the performance of CAR-T cell therapies in treating both blood and solid tumors. The study, published in Nature Chemical Biology, introduces the use of Intrinsically Disordered Regions (IDRs)—specific protein segments that lack a fixed structure—to augment the functionality of chimeric antigen receptors (CARs) on T cells.

Conventional CAR-T therapies often face limitations in targeting cancers with low antigen expression, reducing their overall effectiveness. The Yale team fused IDRs from proteins such as FUS, EWS, and TAF15 to the CARs, which enhanced the cells’ ability to detect and eliminate cancer cells, especially those presenting minimal antigen signals. This innovative approach amplifies weak signals from cancer antigens, resulting in more potent T cell responses.

The researchers demonstrated the effectiveness of this strategy through experiments in cell cultures and mouse models. The modified CAR-T cells showed substantially increased cytotoxic activity against various cancer types, including low-antigen-expressing colorectal cancers, with reduced markers of exhaustion like PD1 and LAG3. Notably, these improvements were observed in models of both blood cancers and solid tumors.

Dr. Xiaolei Su, the senior author and associate professor at Yale School of Medicine, highlighted that this discovery opens new avenues for CAR-T cell design. Since approximately half of human proteins contain IDRs, there is a vast potential for exploring these regions to refine immune cell therapies. The team plans to screen additional IDRs with diverse properties to optimize personalized treatments targeting different cancer types.

Beyond oncology, the strategy of harnessing IDRs could be adapted to enhance other immune receptors, potentially benefiting therapies for infectious diseases, autoimmune conditions, and fibrotic disorders.

This breakthrough underscores the promise of modular protein design in advancing immunotherapy efficacy and paves the way for more versatile and effective cancer treatments.