1. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors.
- Author
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Reinhard K, Rengstl B, Oehm P, Michel K, Billmeier A, Hayduk N, Klein O, Kuna K, Ouchan Y, Wöll S, Christ E, Weber D, Suchan M, Bukur T, Birtel M, Jahndel V, Mroz K, Hobohm K, Kranz L, Diken M, Kühlcke K, Türeci Ö, and Sahin U
- Subjects
- 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, Cancer Vaccines therapeutic use, Claudins antagonists & inhibitors, Immunotherapy, Adoptive methods, Receptors, Chimeric Antigen immunology
- 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., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2020
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