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

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Science  12 Jul 2019:
Vol. 365, Issue 6449, pp. 162-168
DOI: 10.1126/science.aav8692

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A boost for CAR–T cells

Chimeric antigen receptor (CAR)–T cell immunotherapy has been highly successful for treating certain blood cancers. Yet this approach has been a challenge for solid tumors, in part because it is difficult to target functional engineered T cells to the tumor site. Ma et al. designed a vaccine strategy to improve the efficacy of CAR–T cells by restimulating the CAR directly within the native lymph node microenvironment (see the Perspective by Singh and June). Injected “amph-ligand” vaccines promoted synthetic antigen presentation and led to CAR–T cell activation, expansion, and increased tumor killing. The system could potentially be applied to boost any CAR–T cell.

Science, this issue p. 162; see also p. 119

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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