• Hyeon Joo Yoo, Yibin Liu, Lei Wang, Maria-Luisa Schubert, Jean-Marc Hoffmann, Sanmei Wang, Brigitte Neuber, Angela Hückelhoven-Krauss, Ulrike Gern, Anita Schmitt, Carsten Müller-Tidow, Peter Dreger, Andriy Mokhir, Michael Schmitt, and Leopold Sellner.
• Department of Internal Medicine V, Heidelberg University Hospital, 69120 Heidelberg, Germany. hyeonjoo_7@hotmail.com.
• Int J Mol Sci. 2019 May 18; 20 (10).

AbstractChimeric antigen receptor T cell (CART) therapy is currently one of the most promising treatment approaches in cancer immunotherapy. However, the immunosuppressive nature of the tumor microenvironment, in particular increased reactive oxygen species (ROS) levels, provides considerable limitations. In this study, we aimed to exploit increased ROS levels in the tumor microenvironment with prodrugs of ROS accelerators, which are specifically activated in cancer cells. Upon activation, ROS accelerators induce further generation of ROS. This leads to an accumulation of ROS in tumor cells. We hypothesized that the latter cells will be more susceptible to CARTs. CD19-specific CARTs were generated with a CD19.CAR.CD28.CD137zeta third-generation retroviral vector. Cytotoxicity was determined by chromium-51 release assay. Influence of the ROS accelerators on viability and phenotype of CARTs was determined by flow cytometry. The combination of CARTs with the ROS accelerator PipFcB significantly increased their cytotoxicity in the Burkitt lymphoma cell lines Raji and Daudi, as well as primary chronic lymphocytic leukemia cells. Exposure of CARTs to PipFcB for 48 h did not influence T cell exhaustion, viability, or T cell subpopulations. In summary, the combination of CARTs with ROS accelerators may improve adoptive immunotherapy and help to overcome tumor microenvironment-mediated treatment resistance.

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