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Science. 2019 Jul 12;365(6449):162-168. doi: 10.1126/science.aav8692.

Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor.

Author information

1
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
3
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
4
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
5
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. djirvine@mit.edu.
6
Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
7
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Abstract

Chimeric antigen receptor-T cell (CAR-T) therapy has been effective in the treatment of hematologic malignancies, but it has shown limited efficacy against solid tumors. Here we demonstrate an approach to enhancing CAR-T function in solid tumors by directly vaccine-boosting donor cells through their chimeric receptor in vivo. We designed amphiphile CAR-T ligands (amph-ligands) that, upon injection, trafficked to lymph nodes and decorated the surfaces of antigen-presenting cells, thereby priming CAR-Ts in the native lymph node microenvironment. Amph-ligand boosting triggered massive CAR-T expansion, increased donor cell polyfunctionality, and enhanced antitumor efficacy in multiple immunocompetent mouse tumor models. We demonstrate two approaches to generalizing this strategy to any chimeric antigen receptor, enabling this simple non-human leukocyte antigen-restricted approach to enhanced CAR-T functionality to be applied to existing CAR-T designs.

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