RT Journal Article
SR Electronic
T1 CD47 expression is critical for CAR T-cell survival in vivo
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e005857
DO 10.1136/jitc-2022-005857
VO 11
IS 3
A1 Alex N Beckett
A1 Peter Chockley
A1 Shondra M Pruett-Miller
A1 Phuong Nguyen
A1 Peter Vogel
A1 Heather Sheppard
A1 Giedre Krenciute
A1 Stephen Gottschalk
A1 Christopher DeRenzo
YR 2023
UL http://jitc.bmj.com/content/11/3/e005857.abstract
AB 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 ‘sine qua non’ for successful adoptive T-cell therapy.Data are available upon reasonable request.