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Evaluation of a Fully Human, Hepatitis B Virus-Specific Chimeric Antigen Receptor in an Immunocompetent Mouse Model.

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.

SUBMITTER: Festag MM

PROVIDER: S-EPMC6520494 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Evaluation of a Fully Human, Hepatitis B Virus-Specific Chimeric Antigen Receptor in an Immunocompetent Mouse Model.

Festag Marvin M MM Festag Julia J Fräßle Simon P SP Asen Theresa T Sacherl Julia J Schreiber Sophia S Mück-Häusl Martin A MA Busch Dirk H DH Wisskirchen Karin K Protzer Ulrike U

Molecular therapy : the journal of the American Society of Gene Therapy 20190210 5

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 wo ...[more]

PMID: 30852138

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Project description:Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited.To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)-modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity.In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children's Hospital, patients with progressive HER2-positive glioblastoma were enrolled between July 25, 2011, and April 21, 2014. The duration of follow-up was 10 weeks to 29 months (median, 8 months).Monotherapy with autologous VSTs specific for cytomegalovirus, Epstein-Barr virus, or adenovirus and genetically modified to express HER2-CARs with a CD28.?-signaling endodomain (HER2-CAR VSTs).Primary end points were feasibility and safety. The key secondary end points were T-cell persistence and their antiglioblastoma activity.A total of 17 patients (8 females and 9 males; 10 patients ?18 years [median age, 60 years; range, 30-69 years] and 7 patients <18 years [median age, 14 years; range, 10-17 years]) with progressive HER2-positive glioblastoma received 1 or more infusions of autologous HER2-CAR VSTs (1?×?106/m2 to 1?×?108/m2) without prior lymphodepletion. Infusions were well tolerated, with no dose-limiting toxic effects. HER2-CAR VSTs were detected in the peripheral blood for up to 12 months after the infusion by quantitative real-time polymerase chain reaction. Of 16 evaluable patients (9 adults and 7 children), 1 had a partial response for more than 9 months, 7 had stable disease for 8 weeks to 29 months, and 8 progressed after T-cell infusion. Three patients with stable disease are alive without any evidence of progression during 24 to 29 months of follow-up. For the entire study cohort, median overall survival was 11.1 months (95% CI, 4.1-27.2 months) from the first T-cell infusion and 24.5 months (95% CI, 17.2-34.6 months) from diagnosis.Infusion of autologous HER2-CAR VSTs is safe and can be associated with clinical benefit for patients with progressive glioblastoma. Further evaluation of HER2-CAR VSTs in a phase 2b study is warranted as a single agent or in combination with other immunomodulatory approaches for glioblastoma.

Dataset Information

Evaluation of a Fully Human, Hepatitis B Virus-Specific Chimeric Antigen Receptor in an Immunocompetent Mouse Model.

Publications

Evaluation of a Fully Human, Hepatitis B Virus-Specific Chimeric Antigen Receptor in an Immunocompetent Mouse Model.

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