Simonetta et al. showed that control of murine lymphomas by allogeneic CD19 CAR iNKT cells was greater in partially lymphopenic immunocompetent mice than in immunodeficient host mice, and better than that mediated by murine CD19 CAR T cells. Host CD103+CD8α+ DCs enabled CD8+ T cell cross-priming, and in an autologous bone marrow transplant model, allogeneic CAR iNKT and autologous CD8+ T cells synergized to improve tumor control, which was long lasting. CAR-iNKT cells induced prolonged expansion of central memory splenic CD8+ T cells with upregulated cytotoxic activity genes, a downregulated IFN-I signature, and higher TCR clonality.
Contributed by Paula Hochman
Purpose: The development of allogeneic chimeric antigen receptor (CAR) T cell therapies for off-the-shelf use is a major goal yet faces two main immunological challenges, namely the risk of graft-versus-host-disease (GvHD) induction by the transferred cells and the rejection by the host immune system limiting their persistence. In this work we assessed the direct and indirect antitumor effect of allogeneic CAR-engineered invariant natural killer T (iNKT) cells, a cell population without GvHD-induction potential that displays immunomodulatory properties. Experimental Design: After assessing murine CAR iNKT cells direct antitumor effects in vitro and in vivo, we employed an immunocompetent mouse model of B-cell lymphoma to assess the interaction between allogeneic CAR iNKT cells and endogenous immune cells. Results: We demonstrate that allogeneic CAR iNKT cells exerted potent direct and indirect antitumor activity when administered across major MHC-barriers by inducing tumor-specific antitumor immunity through host CD8 T cell cross-priming. Conclusions: In addition to their known direct cytotoxic effect, allogeneic CAR iNKT cells induce host CD8 T cell antitumor responses resulting in a potent antitumor effect lasting longer than the physical persistence of the allogeneic cells. The utilization of off-the-shelf allogeneic CAR iNKT cells could meet significant unmet needs in the clinic.
Author Info: (1) Medicine/BBMT, Stanford University. (2) Medicine/BBMT, Stanford University. (3) Medicine/BBMT, Stanford University. (4) Medicine/BBMT, Stanford University. (5) Medicine/BBMT, S
Author Info: (1) Medicine/BBMT, Stanford University. (2) Medicine/BBMT, Stanford University. (3) Medicine/BBMT, Stanford University. (4) Medicine/BBMT, Stanford University. (5) Medicine/BBMT, Stanford University. (6) Medicine/BBMT, Stanford University. (7) BMT, Stanford. (8) Bioengineering, Stanford University School of Medicine. (9) Genetics, Stanford University. (10) Immunology, Stanford University. (11) Pediatrics, Stanford University. (12) Medicine/BBMT, Stanford University negrs@stanford.edu.
