Zhang et al. developed and optimized a tumor antigen-agnostic CAR T cell therapy using intratumoral administration of a target ligand conjugated to an amphiphile that inserts itself into cell membranes, labeling cells (mostly tumor cells, but some local immune cells) with the non-immunogenic target FITC. In syngeneic and human xenograft solid tumor models, FITC-targeted CAR T cells proliferated and accumulated in amph–FITC-labeled tumors, mediated antitumor effects, extended survival, and induced epitope spreading and endogenous antitumor T cell responses, which mediated abscopal effects and long-term protection from rechallenge.
Contributed by Lauren Hitchings
ABSTRACT: The effectiveness of chimaeric antigen receptor (CAR) T cell therapies for solid tumours is hindered by difficulties in the selection of an effective target antigen, owing to the heterogeneous expression of tumour antigens and to target antigen expression in healthy tissues. Here we show that T cells with a CAR specific for fluorescein isothiocyanate (FITC) can be directed against solid tumours via the intratumoural administration of a FITC-conjugated lipid-poly(ethylene)-glycol amphiphile that inserts itself into cell membranes. In syngeneic and human tumour xenografts in mice, 'amphiphile tagging' of tumour cells drove tumour regression via the proliferation and accumulation of FITC-specific CAR T cells in the tumours. In syngeneic tumours, the therapy induced the infiltration of host T cells, elicited endogenous tumour-specific T cell priming and led to activity against distal untreated tumours and to protection against tumour rechallenge. Membrane-inserting ligands for specific CARs may facilitate the development of adoptive cell therapies that work independently of antigen expression and of tissue of origin.
Author Info: (1) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. Department of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. Dep
Author Info: (1) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. Department of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biophysics, Harvard University, Cambridge, MA, USA. (2) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (3) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (4) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (5) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. (6) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (7) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (8) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. (9) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. (10) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. (11) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. (12) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. (13) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. (14) Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. djirvine@mit.edu. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. djirvine@mit.edu. Ragon Institute of MIT, MGH, and Harvard, Cambridge, MA, USA. djirvine@mit.edu. Howard Hughes Medical Institute, Chevy Chase, MD, USA. djirvine@mit.edu.
