Administering CAR-T cells or T cells with engineered antigen receptors together with antibodies that block the CD47–SiRPα axis—which transmits a “don’t eat me” signal to macrophages—should be a promising therapeutic strategy. But Ludwig Stanford’s Crystal Mackall and her colleagues reported in a Nature paper in May that the combination leads in animal models to rapid clearance of both types of therapeutic T cells by macrophages, which appear to help regulate T cell persistence in tumors. The researchers noted that clearance of CAR-T cells bound by anti-CD47 antibody was in fact so swift and thorough that it could serve as a safety switch to shut down CAR-T cells if necessary. To fix the problem, the researchers engineered therapeutic T cells to express a CD47 mutant (CD47E) that is still bound and activated by SiRPα but is not recognized by anti-CD47 antibodies. This protected the therapeutic T cells and CAR-T cells from macrophages by their continuing transmission of the “don’t eat me” signal while leaving tumor cells susceptible to macrophage targeting after treatment with anti-CD47 antibodies. The researchers showed that the combination therapy induces significant and sustained recruitment of macrophages to the tumor, and even though many of these macrophages had pro-tumorigenic properties, the combined treatment proved sufficiently synergistic to enhance anti-tumor effects in mouse models.
Engineered CD47 protects T cells for enhanced antitumour immunity
Nature, 2024 May 15