Hammer et al. showed that deletion of genes for the CD54 (ICAM-1, binds LFA-1) and CD58 (LFA-3, binds CD2) adhesion molecules in B2M-/- (HLA-Ilo) target cells reduced their sensitivity to NK cell “missing-self” responses. To improve persistence of allogeneic cell therapy, B2M-/-CD54-/-CD58-/- CAR+ T cells and B2M-/-CIITA-/-CD54-/-CD58-/- multi-edited iPSC-derived CAR+ NK cells were generated. These CAR+ cells were shown to maintain activity and be hypo-immunogenic in vitro and in vivo, resisting allogeneic rejection by all subsets of host NK cells (regardless of their NK inhibitory receptor repertoire) to enhance CAR+ cell survival and sustain their antitumor activity.
Contributed by Paula Hochman
ABSTRACT: Allogeneic cellular immunotherapies hold promise for broad clinical implementation but face limitations due to potential rejection of donor cells by the host immune system. Silencing of beta-2 microglobulin (B2M) expression is commonly employed to evade T cell-mediated rejection by the host, although the absence of B2M is expected to trigger missing-self responses by host natural killer (NK) cells. Here, we demonstrate that genetic deletion of the adhesion ligands CD54 and CD58 in B2M-deficient chimeric antigen receptor (CAR) T cells and multi-edited induced pluripotent stem cell (iPSC)-derived CAR NK cells reduces their susceptibility to rejection by host NK cells in vitro and in vivo. The absence of adhesion ligands limits rejection in a unidirectional manner in B2M-deficient and B2M-sufficient settings without affecting the antitumor functionality of the engineered donor cells. Thus, these data suggest that genetic ablation of adhesion ligands effectively alleviates rejection by host immune cells, facilitating the implementation of universal immunotherapy.
Author Info: (1) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. Electronic address: quirin.hammer@ki.se. (2) Department of Medicine,
Author Info: (1) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. Electronic address: quirin.hammer@ki.se. (2) Department of Medicine, Weill Cornell Medical College, New York, NY, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Cell Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Fate Therapeutics, Inc., San Diego, CA, USA. (4) Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Solna, Sweden. (5) Precision Immunotherapy Alliance, Institute for Cancer Research, University of Oslo, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. (6) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (7) Fate Therapeutics, Inc., San Diego, CA, USA. (8) Fate Therapeutics, Inc., San Diego, CA, USA. (9) Fate Therapeutics, Inc., San Diego, CA, USA. (10) Fate Therapeutics, Inc., San Diego, CA, USA. (11) Fate Therapeutics, Inc., San Diego, CA, USA. (12) Precision Immunotherapy Alliance, Institute for Cancer Research, University of Oslo, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. (13) Fate Therapeutics, Inc., San Diego, CA, USA. (14) Fate Therapeutics, Inc., San Diego, CA, USA. (15) Fate Therapeutics, Inc., San Diego, CA, USA. (16) Fate Therapeutics, Inc., San Diego, CA, USA. (17) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Solna, Sweden. (18) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (19) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Precision Immunotherapy Alliance, Institute for Cancer Research, University of Oslo, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. Electronic address: k.j.malmberg@medisin.uio.no.
