@article {Beckette005857, author = {Alex N Beckett and Peter Chockley and Shondra M Pruett-Miller and Phuong Nguyen and Peter Vogel and Heather Sheppard and Giedre Krenciute and Stephen Gottschalk and Christopher DeRenzo}, title = {CD47 expression is critical for CAR T-cell survival in vivo}, volume = {11}, number = {3}, elocation-id = {e005857}, year = {2023}, doi = {10.1136/jitc-2022-005857}, publisher = {BMJ Specialist Journals}, abstract = {Background CD47 is an attractive immunotherapeutic target because it is highly expressed on multiple solid tumors. However, CD47 is also expressed on T cells. Limited studies have evaluated CD47-chimeric antigen receptor (CAR) T cells, and the role of CD47 in CAR T-cell function remains largely unknown.Methods Here, we describe the development of CD47-CAR T cells derived from a high affinity signal regulatory protein α variant CV1, which binds CD47. CV1-CAR T cells were generated from human peripheral blood mononuclear cells and evaluated in vitro and in vivo. The role of CD47 in CAR T-cell function was examined by knocking out CD47 in T cells followed by downstream functional analyses.Results While CV1-CAR T cells are specific and exhibit potent activity in vitro they lacked antitumor activity in xenograft models. Mechanistic studies revealed CV1-CAR T cells downregulate CD47 to overcome fratricide, but CD47 loss resulted in their failure to expand and persist in vivo. This effect was not limited to CV1-CAR T cells, since CD47 knockout CAR T cells targeting another solid tumor antigen exhibited the same in vivo fate. Further, CD47 knockout T cells were sensitive to macrophage-mediated phagocytosis.Conclusions These findings highlight that CD47 expression is critical for CAR T-cell survival in vivo and is a {\textquoteleft}sine qua non{\textquoteright} for successful adoptive T-cell therapy.Data are available upon reasonable request.}, URL = {https://jitc.bmj.com/content/11/3/e005857}, eprint = {https://jitc.bmj.com/content/11/3/e005857.full.pdf}, journal = {Journal for ImmunoTherapy of Cancer} }