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Evaluation of a fully human, hepatitis B virus-specific chimeric antigen receptor in an immunocompetent mouse model.

Mol. Ther. 27, 947-959 (2019)
Postprint online available 03/2020 Open Access Green as soon as is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Aav ; Car ; Hbv ; T Cell Therapy ; Chimeric Antigen Receptor ; Immunocompetent Mice ; Immunotherapy ; Rejection ; Scfv Expression; Car-t-cells; Reactivation; Replication; Mechanisms; Tolerance; Therapy; Cd19; Challenges; Induction; Injection
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