Mol Ther. 2019 Feb 10. pii: S1525-0016(19)30042-5. doi: 10.1016/j.ymthe.2019.02.001. [Epub ahead of print]
Evaluation of a Fully Human, Hepatitis B Virus-Specific Chimeric Antigen Receptor in an Immunocompetent Mouse Model.
Festag MM1, Festag J1, Fräßle SP2, Asen T1, Sacherl J1, Schreiber S1, Mück-Häusl MA1, Busch DH3, Wisskirchen K4, Protzer U5.
Author information
1
Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, 81675 Munich, Germany.
2
Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, 81675 Munich, Germany.
3
Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, 81675 Munich, Germany; German Center for Infection Research (DZIF), Munich partner site, 81675 Munich, Germany.
4
Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, 81675 Munich, Germany; German Center for Infection Research (DZIF), Munich partner site, 81675 Munich, Germany. Electronic address: [email protected].
5
Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, 81675 Munich, Germany; German Center for Infection Research (DZIF), Munich partner site, 81675 Munich, Germany. Electronic address: [email protected].
Abstract
Chimeric antigen receptor (CAR) T cell therapy is a promising novel therapeutic approach for cancer but also for chronic infection. We have developed a fully human, second-generation CAR directed against the envelope protein of hepatitis B virus on the surface of infected cells (S-CAR). The S-CAR contains a human B cell-derived single-chain antibody fragment and human immunoglobulin G (IgG) spacer, CD28- and CD3-signaling domains that may be immunogenic in mice. Because immunosuppression will worsen the clinical course of chronic hepatitis B, we aimed at developing a preclinical mouse model that is immunocompetent and mimics chronic hepatitis B but nevertheless allows evaluating efficacy and safety of a fully human CAR. The S-CAR grafted on T cells triggered antibody responses in immunocompetent animals, and a co-expressed human-derived safeguard, the truncated epidermal growth factor receptor (EGFRt), even induced B and T cell responses, both limiting the survival of S-CAR-grafted T cells. Total body irradiation and transfer of T cells expressing an analogous, signaling-deficient S-CAR decoy and the safeguard induced immune tolerance toward the human-derived structures. S-CAR T cells transferred after immune recovery persisted and showed long-lasting antiviral effector function. The approach we describe herein will enable preclinical studies of efficacy and safety of fully human CARs in the context of a functional immune system.