589 Enhancement of the anti-tumor effects of CD47 blockade in solid tumors by combination with targeted radioimmunotherapy

Background One mechanism that tumors use to escape immunosurveillance is the overexpression of CD47, which inhibits macrophage mediated phagocytosis pathway. Although blockade CD47-SIRPα axis a promising approach enhance tumor targeted phagocytosis, anti-CD47 monotherapies have not shown meaningful responses in clinical studies solid tumors. Combination cancer therapies aim increase probability response settings resistance by combining drugs with different mechanisms action. Antibody radioconjugates (ARCs) specifically target and deliver therapeutic radiation directly cells. We rationalized immunogenic cytotoxic properties ARCs will upregulate calreticulin (CRT), pro-phagocytic signal, thereby synergizing CD47 blocking antitumor activity. Here for first time, we demonstrate combination benefit HER2 specific targeting ARC antibody efficacy preclinical models. Methods The anti-HER2 trastuzumab was conjugated p-SCN-DOTA radiolabeled Ac-225 or Lu-177. biological activity both evaluated using human recombinant receptor positive cell lines. effect ability CRT XTT assay flow cytometry, respectively, panel expressing To evaluate synergy vitro, cytometry developed. further vivo between xenograft mouse model. Results similar binding native cytotoxicity. Importantly, observe ARC-mediated upregulation Furthermore, enhances vitro compared each agent alone. Remarkably, shows enhanced reduced toxicity improved survival Conclusions an finding suggests potentiates signal synergizes mode action enhancing immune response. This provides very strategy improve patients harboring warrants evaluation. Ethics Approval All animal experiments were approved IACUC.