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Two approaches to improve ACT are TCR affinity optimization and T cell coengineering to express immunomodulatory molecules that can exploit endogenous immunity. By computational design we previously developed a panel of binding-enhanced A2\/NY-TCRs including A97L, which augmented the in vitro function of gene-modified T cells as compared with WT. Here, we demonstrated higher persistence and improved tumor control by A97L\u2013T cells. In order to harness macrophages in tumors, we further coengineered A97L\u2013T cells to secrete a high-affinity signal regulatory protein \u03b1 (SiRP\u03b1) decoy (CV1) that blocks CD47. While CV1-Fc\u2013coengineered A97L\u2013T cells mediated significantly better control of tumor outgrowth and survival in Winn assays, in subcutaneous xenograft models the T cells, coated by CV1-Fc, were depleted. Importantly, there was no phagocytosis of CV1 monomer\u2013coengineered T cells by human macrophages. Moreover, avelumab and cetuximab enhanced macrophage-mediated phagocytosis of tumor cells in vitro in the presence of CV1 and improved tumor control upon coadministration with A97L\u2013T cells. Taken together, our study indicates important clinical promise for harnessing macrophages by combining CV1-coengineered TCR\u2013T cells with targeted antibodies to direct phagocytosis against tumor cells.\n                  <\/jats:p>","DOI":"10.1172\/jci161660","type":"journal-article","created":{"date-parts":[[2024,6,2]],"date-time":"2024-06-02T14:00:32Z","timestamp":1717336832000},"source":"Crossref","is-referenced-by-count":20,"title":["Combining SiRP\u03b1 decoy\u2013coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells"],"prefix":"10.1172","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8750-5954","authenticated-orcid":true,"given":"Evangelos","family":"Stefanidis","sequence":"first","affiliation":[{"name":"Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland."},{"name":"Department of Molecular Biology and Genetics, 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