Investigator
University Of Chicago
A universal chimeric antigen receptor (CAR)–fragment antibody binder (FAB) split system for cancer immunotherapy
Chimeric antigen receptor (CAR) T cell therapy has shown extraordinary results in treating hematological cancer but faces challenges like antigen loss, toxicity, and complex manufacturing. Universal and modular CAR constructs offer improved flexibility, safety, and cost-effectiveness over conventional CAR constructs. We present a CAR–fragment antibody binder (Fab) platform on the basis of an engineered protein G variant (GA1) and Fab scaffolds. Expression of GA1CAR on human CD8 + T cells leads to antigen recognition and T cell effector function that can be modulated according to the affinity of the CAR for the Fab and of the Fab for the target. GA1CAR T cells can recognize multiple Fab-antigen pairs on breast and ovarian cancer cell lines. Adoptively transferred GA1CAR T cells control tumors in breast cancer xenograft models, and their targeting can be quickly redirected using different Fabs. This versatile “plug-and-play” CAR T platform has potential for application in personalized therapy, preventing antigen loss variant escape, decreasing toxicity, and increasing access.
NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity
Tumors are surrounded by supportive cells called cancer-associated fibroblasts (CAFs), which normally help protect the tumor from the immune system. The researchers found that an enzyme in these fibroblasts, called NNMT, is a key driver of this protection: it triggers the release of immune-suppressing molecules that recruit "suppressor" immune cells to shield the tumor from attack, particularly in high-grade serous ovarian cancer, the most common and deadly form of ovarian cancer.
