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Science ; 367(6476): 446-453, 2020 01 24.
Article in English | MEDLINE | ID: mdl-31896660

ABSTRACT

Chimeric antigen receptor (CAR)-T cells have shown efficacy in patients with B cell malignancies. Yet, their application for solid tumors has challenges that include limited cancer-specific targets and nonpersistence of adoptively transferred CAR-T cells. Here, we introduce the developmentally regulated tight junction protein claudin 6 (CLDN6) as a CAR target in solid tumors and a strategy to overcome inefficient CAR-T cell stimulation in vivo. We demonstrate that a nanoparticulate RNA vaccine, designed for body-wide delivery of the CAR antigen into lymphoid compartments, stimulates adoptively transferred CAR-T cells. Presentation of the natively folded target on resident antigen-presenting cells promotes cognate and selective expansion of CAR-T cells. Improved engraftment of CAR-T cells and regression of large tumors in difficult-to-treat mouse models was achieved at subtherapeutic CAR-T cell doses.


Subject(s)
Cancer Vaccines/therapeutic use , Claudins/antagonists & inhibitors , Immunotherapy, Adoptive/methods , Receptors, Chimeric Antigen/immunology , Animals , Claudins/immunology , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , RNA/therapeutic use , T-Lymphocytes/immunology , T-Lymphocytes/transplantation , Vaccines, Synthetic/therapeutic use
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