Zhou et al. showed that human CD19-targeted murine CAR-NKT and CAR-T cells exhibited comparable antitumor activity in vitro, but CAR-NKT cell treatment provided greater efficacy in multiple immunocompetent solid tumor models. CAR-NKT cell treatment altered the TME by reducing M2-like macrophages and activating DCs to promote responses and epitope spreading to endogenous T cells in a CD1d-dependent manner, complementing direct CAR-NKT cell activity. PD-1+Tim3+ exhausted CAR-NKT cells were detected in a model of high tumor burden. PD-1 blockade and α-GalCer vaccination boosted CAR-NKT cell antitumor activity.
Contributed by Paula Hochman
ABSTRACT: Human natural killer T (NKT) cells have been proposed as a promising cell platform for chimeric antigen receptor (CAR) therapy in solid tumors. Here we generated murine CAR-NKT cells and compared them with CAR-T cells in immune-competent mice. Both CAR-NKT cells and CAR-T cells showed similar antitumor effects in vitro, but CAR-NKT cells showed superior antitumor activity in vivo via CD1d-dependent immune responses in the tumor microenvironment. Specifically, we show that CAR-NKT cells eliminate CD1d-expressing M2-like macrophages. In addition, CAR-NKT cells promote epitope spreading and activation of endogenous T cell responses against tumor-associated neoantigens. Finally, we observed that CAR-NKT cells can co-express PD1 and TIM3 and show an exhaustion phenotype in a model of high tumor burden. PD1 blockade as well as vaccination augmented the antitumor activity of CAR-NKT cells. In summary, our results demonstrate the multimodal function of CAR-NKT cells in solid tumors, further supporting the rationale for developing CAR-NKT therapies in the clinic.
Author Info: (1) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill
Author Info: (1) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA. (2) Center for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. (3) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. (4) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (5) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. (6) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. (7) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. (8) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. (9) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Division of Oncology, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, USA. (10) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (11) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (12) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Division of Oncology, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, USA. (13) Center for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. (14) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA. (15) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA. (16) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA. (17) Center for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. (18) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. gdotti@med.unc.edu. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA. gdotti@med.unc.edu.
