12 July 2019 Vol 365, Issue 6449
Enhanced CAR–T cell activity against solid tumors by vaccine boosting through the chimeric receptor
By Leyuan Ma, Tanmay Dichwalkar, Jason Y. H. Chang, Benjamin Cossette, Daniel Garafola, Angela Q. Zhang, Michael Fichter, Chensu Wang, Simon Liang, Murillo Silva, Sudha Kumari, Naveen K. Mehta, Wuhbet Abraham, Nikki Thai, Na Li, K. Dane Wittrup, Darrell J. Irvine
Science12 Jul 2019 : 162-168 Restricted Access
Vaccine boosting enhances chimeric antigen receptor–T cell immunotherapy for cancer.
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.
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.