Engineered CD47 enhances antitumor immunity by inducing selective tumor phagocytosis while sparing T cells

Adoptively transferred T cells and agents designed to block the CD47/SIRPa axis are promising antitumor therapeutics, which activate distinct arms of the immune system. We administered anti-CD47 (aCD47) with adoptively transferred T cells with the goal of enhancing antitumor efficacy but observed rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors, which blunted therapeutic benefit. aCD47 mediated CAR T clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered a CD47 variant (47E) that engaged SIRPa and provided dont-eat-me signals but was not blocked by aCD47 antibodies. Adoptive transfer of TCR or CAR T cells expressing 47E were resistant to macrophage mediated ablation following aCD47, and mediated significant, sustained macrophage recruitment into the TME. Although many of the recruited macrophages manifested an M2-like profile, the combined therapy resulted in synergistic enhancement in antitumor efficacy. This work identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T cell directed therapeutics with those designed to activate macrophages. It further delivers a therapeutic approach capable of simultaneously harnessing the antitumor effects of T cells and macrophages that manifests markedly enhanced potency against solid tumors.