USC researchers have developed a new type of chimeric antigen receptor (CAR) T cell that elicits a more controlled immune response to cancer in mice—effectively killing cancer cells, including those that typically escape detection, with fewer toxic side effects. The engineered CAR T cells may someday offer a way to more safely treat blood cancers and reduce the chance of relapse. CAR T cells express a receptor on the cell surface that recognizes cancer cells and signaling molecules inside the cell that activate the immune response. To address the safety and efficacy issues with existing CAR T therapies, researchers focused on redesigning the second component—the cell’s internal signaling machinery. Current FDA-approved CAR T cell products use the same signaling protein—CD3 zeta chain, or CD3ζ—to activate T cells for cancer destruction. While they often work well, these cells can lose strength too quickly and may not survive long in the body, which means some patients will see their cancer return. To look for a safer and more effective alternative, the researchers screened molecules involved early in the T-cell signaling process—proteins that help guide how strongly and how long T cells stay activated. One molecule, ZAP70, stood out for its ability to strongly activate CAR T cells without overstimulating them. The researchers tested several forms of the molecule and found that one piece, known as ZAP327, provided the best balance of safety and potency. The team then replaced CD3ζ with ZAP327 to create the next-generation CAR T cells, known as Synthetic TCR signaling for Enhancing Memory T cells (STEM). In mouse models, the STEM-engineered CAR T cells performed as well as or better against cancer cells than FDA-approved CAR T cells and other new varieties - and kept their cancer-fighting abilities for longer. This suggests they may be more effective at recognizing and preventing disease relapse after remission.
