Ma et al. explored whether a lymph node-targeting, CAR-T target-bearing vaccine shown to improve CAR-T efficacy could induce antigen spreading in tumor models. CAR-T plus vaccination raised host T cell responses against non-CAR-targeted tumor antigens and increased infiltration of activated APCs and host CD8+ T cells, which were enriched in a cytotoxic phenotype. Dual therapy altered CAR-T phenotype (effector function, OXPHOS) and enabled tumor control, even of mixed-antigen tumors, dependent on endogenous T cells, IL-12, and CAR-T-secreted IFNγ. CAR-T cells with NFAT-driven IFNγ improved efficacy over standard CAR-T.
Contributed by Alex Najibi
ABSTRACT: Chimeric antigen receptor (CAR) T cell therapy effectively treats human cancer, but the loss of the antigen recognized by the CAR poses a major obstacle. We found that in vivo vaccine boosting of CAR T cells triggers the engagement of the endogenous immune system to circumvent antigen-negative tumor escape. Vaccine-boosted CAR T promoted dendritic cell (DC) recruitment to tumors, increased tumor antigen uptake by DCs, and elicited the priming of endogenous anti-tumor T cells. This process was accompanied by shifts in CAR T metabolism toward oxidative phosphorylation (OXPHOS) and was critically dependent on CAR-T-derived IFN-γ. Antigen spreading (AS) induced by vaccine-boosted CAR T enabled a proportion of complete responses even when the initial tumor was 50% CAR antigen negative, and heterogeneous tumor control was further enhanced by the genetic amplification of CAR T IFN-γ expression. Thus, CAR-T-cell-derived IFN-γ plays a critical role in promoting AS, and vaccine boosting provides a clinically translatable strategy to drive such responses against solid tumors.
Author Info: (1) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University
Author Info: (1) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: leyuan.ma@pennmedicine.upenn.edu. (2) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA. (3) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Chemical Engineering, MIT, Cambridge, MA, USA. (4) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA. (5) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA. (6) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA. (7) Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA. (8) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA. (9) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA. (10) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA. (11) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA. (12) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA. (13) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA. (14) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA. (15) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA. (16) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Chemical Engineering, MIT, Cambridge, MA, USA; Ragon Institute of Massachusetts General Hospital, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (17) David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Materials Science and Engineering, MIT, Cambridge, MA 02139, USA; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA; Ragon Institute of Massachusetts General Hospital, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: djirvine@mit.edu.
