Evaluation of a Fully Human, Hepatitis B Virus-Specific Chimeric Antigen Receptor in an Immunocompetent Mouse Model.
Animals
B-Lymphocytes
/ drug effects
CD28 Antigens
/ immunology
CD3 Complex
/ immunology
Disease Models, Animal
Hepatitis B
/ genetics
Hepatitis B virus
/ genetics
Humans
Immunocompetence
/ drug effects
Immunoglobulin G
/ immunology
Mice
Receptors, Chimeric Antigen
/ administration & dosage
Single-Chain Antibodies
/ chemistry
T-Lymphocytes
/ drug effects
Viral Envelope Proteins
/ antagonists & inhibitors
AAV
CAR
HBV
T cell therapy
chimeric antigen receptor
immunocompetent mice
immunotherapy
rejection
scFv expression
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
08 05 2019
08 05 2019
Historique:
received:
29
08
2018
revised:
03
02
2019
accepted:
03
02
2019
pubmed:
11
3
2019
medline:
24
3
2020
entrez:
11
3
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30852138
pii: S1525-0016(19)30042-5
doi: 10.1016/j.ymthe.2019.02.001
pmc: PMC6520494
pii:
doi:
Substances chimiques
CD28 Antigens
0
CD3 Complex
0
Immunoglobulin G
0
Receptors, Chimeric Antigen
0
Single-Chain Antibodies
0
Viral Envelope Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
947-959Informations de copyright
Copyright © 2019. Published by Elsevier Inc.
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