An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors
Katharina Reinhard, Benjamin Rengstl, Petra Oehm, Kristina Michel, Arne Billmeier, Nina Hayduk, Oliver Klein, Kathrin Kuna, Yasmina Ouchan, Stefan Wöll, Elmar Christ, David Weber, M Suchan, Thomas Bukur, Matthias Birtel, Veronika Jahndel, Karolina Mroz, Kathleen Hobohm, Lena M. Kranz, Mustafa Diken, Klaus Kühlcke, Özlem Türeci, Uğur Şahin
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.