Bailey, Takei, Escobar, et al. investigated the effects of inhibition of IFN signaling in CAR T cells. Knockout of IFNγ or IFNγR increased expansion and persistence of CAR T cells with a CD28 costimulatory domain, which was found to be due to reduced IFNγ-induced cell death. In murine solid tumor models, IFNγ-KO CAR T cells had reduced antitumor activity, while IFNγR-KO CAR T cells had increased antitumor activity, resulting in better survival. Additionally, IFNγR-KO CAR T cells provided protection against rechallenge in cured mice.
ABSTRACT: Interferon-γ (IFN-γ) plays complex and, sometimes, contradictory roles in cancer, which can affect patient responses to treatments such as immunotherapies. We recently demonstrated that IFN-γ production by chimeric antigen receptor (CAR) T cells is not required for efficacy in hematologic tumor models, whereas IFN-γ receptor (IFN-γR) signaling in solid tumor cells facilitates CAR T cell adhesion and antigen-specific cytotoxicity. Here, we show that IFN-γ induces apoptosis of CAR T cells bearing a CD28 intracellular signaling domain, which can be reduced through targeting of IFN-γ or IFN-γR. In hematologic malignancies, knockout of IFN-γR (IFN-γRKO) in CAR T cells increased their persistence without compromising efficacy. In xenograft and syngeneic solid tumor models, IFN-γR knockout CAR T cells displayed more potent tumor control, prolonged survival, and improved T cell memory that conferred protection from tumor rechallenge. RNA sequencing of tumor-infiltrating IFN-γRKO CAR T cells derived from tumor-bearing mice revealed increased cell death in tumor cells. Collectively, these data show that inhibition of IFN-γ signaling can increase the expansion and antitumor activity of CD28-based CAR T cells in liquid and solid tumors.
Author Info: (1) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (2)
Author Info: (1) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (2) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. (3) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. (4) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. (5) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. (6) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (7) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. (8) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. (9) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (10) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (11) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (12) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. (13) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. (14) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (15) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. (16) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (17) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (18) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (19) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (20) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (21) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. (22) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02129, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
