Combination of NY-ESO-1-TCR-T-cells coengineered to secrete SiRPα decoys with anti-tumor antibodies to augment macrophage phagocytosis

The adoptive transfer of T cell receptor (TCR)-engineered T cells (ACT) targeting the HLA-A2 restricted cancer-testis epitope NY-ESO-1157-165 (A2/NY) has yielded favorable clinical responses against a variety of cancers. Two promising approaches to improve ACT efficacy are TCR affinity-optimization and combinatorial treatment strategies to reprogram the tumor microenvironment (TME). By computational design, we previously developed a panel of affinity-enhanced A2/NY-TCRs. Here, we have demonstrated improved tumor control and engraftment by T cells gene-modified to express one such TCR comprising a single amino acid replacement in CDR3β (A97L). To harness macrophages in the TME, we coengineered TCR-T cells to constitutively or inducibly secrete a high-affinity signal regulatory protein alpha (SiRPα) decoy (CV1) to block the CD47 ‘don’t eat me’ signal. We demonstrated better control of tumor outgrowth by CV1-Fc coengineered TCR-T cells but in subcutaneous xenograft tumor models we observed depletion of both CV1-Fc and CV1 coengineered T cells. Importantly, CV1 coengineered T cells were not depleted by human macrophages in vitro. Moreover, Avelumab and Cetuximab enhanced macrophage-mediated phagocytosis in vitro in the presence of CV1, and augmented tumor control upon ACT. Taken together, our study indicates important clinical promise for harnessing macrophages by combining CV1 coengineered TCR-T cells with tumor-targeting monoclonal antibodies. ### Competing Interest Statement G.C. has received grants and research support or has been co-investigator in clinical trials by Bristol-Myers Squibb, Tigen Pharma, Iovance, F. Hoffmann La Roche AG and Boehringer Ingelheim. The Lausanne University Hospital (CHUV) has received honoraria for advisory services that G.C. has provided to Genentech, AstraZeneca AG and EVIR. G.C. has previously received royalties from the University of Pennsylvania for CAR-T-cell therapy licensed to Novartis and Tmunity Therapeutics.