Using a genome-wide CRISPR screen, Menegatti et al. identified targets that could extend the persistence of allogeneic C57BL/6 T cells in a BALB/c host. Although disruption of either Fas or B2m improved the survival of allogeneic T cells, Fas KO was more effective than B2m KO in resisting NK cell-mediated allorejection. In human CAR T cells, disruption of TRAC and Fas, compared to TRAC and B2m, improved survival in in vitro and in vivo models of T cell or NK cell-mediated allorejection, and led to superior effector function and tumor control, even without allogeneic pressure.
Contributed by Alex Najibi
ABSTRACT: Allogeneic chimaeric antigen receptor T cells (allo-CAR T cells) derived from healthy donors could provide rapid access to standardized and affordable batches of therapeutic cells if their rejection by the host's immune system is avoided. Here, by means of an in vivo genome-wide CRISPR knockout screen, we show that the deletion of Fas or B2m in allo- T cells increases their survival in immunocompetent mice. Human B2M(-) allo-CAR T cells become highly sensitive to rejection mediated by natural killer (NK) cells, whereas FAS(-) CAR T cells expressing normal levels of human leukocyte antigen I remain resistant to NK cells. CD3(-) FAS(-) CAR T cells outperformed CD3(-) B2M(-) CAR T cells in the control of leukaemia growth in mice under allogeneic pressure by T cells and NK cells. The partial protection of CD3(-) FAS(-) allo-CAR T cells from cellular rejection may improve the efficacy of allogeneic cellular therapies in patients with cancer.
Author Info: (1) Immunity and Cancer, Institut Curie, PSL University, INSERM U932, Paris, France. CellAction (Cell therapy Acceleration and Innovation), Institut Curie, Suresnes, France. (2) Im
Author Info: (1) Immunity and Cancer, Institut Curie, PSL University, INSERM U932, Paris, France. CellAction (Cell therapy Acceleration and Innovation), Institut Curie, Suresnes, France. (2) Immunity and Cancer, Institut Curie, PSL University, INSERM U932, Paris, France. (3) Immunity and Cancer, Institut Curie, PSL University, INSERM U932, Paris, France. (4) Immunity and Cancer, Institut Curie, PSL University, INSERM U932, Paris, France. CellAction (Cell therapy Acceleration and Innovation), Institut Curie, Suresnes, France. (5) Immunity and Cancer, Institut Curie, PSL University, INSERM U932, Paris, France. CellAction (Cell therapy Acceleration and Innovation), Institut Curie, Suresnes, France. (6) Gustave Roussy, Paris-Saclay University, INSERM U1015, Villejuif, France. (7) Immunity and Cancer, Institut Curie, PSL University, INSERM U932, Paris, France. (8) Immunity and Cancer, Institut Curie, PSL University, INSERM U932, Paris, France. CellAction (Cell therapy Acceleration and Innovation), Institut Curie, Suresnes, France. (9) Immunity and Cancer, Institut Curie, PSL University, INSERM U932, Paris, France. (10) Immunity and Cancer, Institut Curie, PSL University, INSERM U932, Paris, France. (11) Immunity and Cancer, Institut Curie, PSL University, INSERM U932, Paris, France. CellAction (Cell therapy Acceleration and Innovation), Institut Curie, Suresnes, France. (12) Gustave Roussy, Paris-Saclay University, INSERM U1015, Villejuif, France. (13) Gustave Roussy, Paris-Saclay University, INSERM U1015, Villejuif, France. (14) Mnemo Therapeutics, Paris, France. (15) Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA. (16) Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA. (17) Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA. (18) Immunity and Cancer, Institut Curie, PSL University, INSERM U932, Paris, France. (19) Immunity and Cancer, Institut Curie, PSL University, INSERM U932, Paris, France. sebastian.amigorena@curie.fr. CellAction (Cell therapy Acceleration and Innovation), Institut Curie, Suresnes, France. sebastian.amigorena@curie.fr. Mnemo Therapeutics, Paris, France. sebastian.amigorena@curie.fr. (20) Gustave Roussy, Paris-Saclay University, INSERM U1015, Villejuif, France. Laurie.MENGER@gustaveroussy.fr.
