(517b) Macrophage Checkpoint Blockade in a Cell-Based Immunotherapy Can Generate Durable and Safe Cures in a Poorly Immunogenic, Syngeneic Mouse Tumor Model

Bone marrow-derived monocytes and macrophages can be engineered to phagocytose opsonized cancer cells by blockade of the inhibitory surface receptor SIRPα which recognizes the “self-marker” CD47 expressed on all cells. Here, we explore this strategy in a cellular immunotherapy targeting syngeneic, orthotopic B16 melanoma in immunocompetent mice. These tumors double in size every two to three days, which is ~100-fold faster than human tumors, but are difficult to treat and regarded as poorly immunogenic, making them refractory to many current immunotherapies including blockade of CD47 with injected antibodies. We harvested marrow cells from donor mice and incubated with (1) anti-SIRPα to block the anti-phagocytic, “don’t eat me” signal, and (2) anti-Tyrp1 against tyrosinase-related-protein-1 on B16 cells. The latter antibody binds Fc-receptors on the marrow monocytes, targeting them to tumors and providing a pro-phagocytic, “eat me” signal. Tail-vein injection of the engineered cells into mice inoculated with B16 cells can prevent tumor growth and result in durable cures, with some cured mice developing long-term adaptive immunity to protect against re-challenge. The approach also avoids safety concerns including anemia that are already evident in the clinic with intravenous anti-CD47 blockade.