Claudin18.2-Specific Chimeric Antigen Receptor Engineered T Cells for the Treatment of Gastric Cancer

Claudin18.2 (CLDN18.2), a gastric-specific membrane protein, has been regarded as a potential therapeutic target for gastric cancer and other cancer types. The aim of our study was to elucidate whether chimeric antigen receptor T (CAR T) cells redirected to CLDN18.2 have the potential to be used in...

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Published in:JNCI : Journal of the National Cancer Institute Vol. 111; no. 4; p. 409
Main Authors: Jiang, Hua, Shi, Zhimin, Wang, Peng, Wang, Cong, Yang, Linlin, Du, Guoxiu, Zhang, Honghong, Shi, Bizhi, Jia, Jie, Li, Qixiang, Wang, Huamao, Li, Zonghai
Format: Journal Article
Language:English
Published: United States 01.04.2019
Subjects:
Animals
Antibodies, Monoclonal, Humanized - pharmacology
Apoptosis
Cell Proliferation
Claudins - genetics
Claudins - immunology
Humans
Immunotherapy, Adoptive - methods
Mice
Receptors, Chimeric Antigen - genetics
Receptors, Chimeric Antigen - immunology
Stomach Neoplasms - immunology
Stomach Neoplasms - therapy
T-Lymphocytes - immunology
T-Lymphocytes - transplantation
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
ISSN:1460-2105, 1460-2105
Online Access:Get more information
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Summary:Claudin18.2 (CLDN18.2), a gastric-specific membrane protein, has been regarded as a potential therapeutic target for gastric cancer and other cancer types. The aim of our study was to elucidate whether chimeric antigen receptor T (CAR T) cells redirected to CLDN18.2 have the potential to be used in the treatment of this deadly disease. CLDN18.2-specific humanized antibodies were developed using hybridoma and humanization technology. CLDN18.2-specific CAR T cells were prepared by lentiviral vector transduction. In vitro antitumor activities and cytokine production of the CAR T cells to gastric cancer cell lines were examined by cytotoxicity and ELISA assay. In vivo antitumor activities of CAR T cells were evaluated in mice bearing gastric cancer cell line and patient-derived tumor xenograft (PDX) models (n ≥ 6 mice per group). All statistical tests were two-sided. Humanized CLDN18.2-specific hu8E5 and hu8E5-2I single-chain fragment variables (scFv) were successfully developed. CLDN18.2-specific CAR T cells were developed using hu8E5 or hu8E5-2I scFv as targeting moieties. Both hu8E5-28Z and hu8E5-2I-28Z CAR T cells comprising the CD28 costimulatory domain potently suppressed tumor growth in a cancer cell line xenograft mouse model (mean [SD] tumor volume: hu8E5-28Z = 118.0 [108.6] mm3 and hu8E5-2I-28Z group = 75.5 [118.7] mm3 vs untransduced T cell group = 731.8 [206.3] mm3 at day 29 after tumor inoculation, P < .001). Partial or complete tumor elimination was observed in CLDN18.2-positive gastric cancer PDX models treated with the hu8E5-2I-28Z CAR T cells (P < .001), which persist well in vivo and infiltrate efficiently into the tumor tissues. Although the CLDN18.2 CAR T cells could lyse target cells expressing murine CLDN18.2 (mCLDN18.2), no obvious deleterious effect on the normal organs including the gastric tissues was observed in the mice. CLDN18.2-specific CAR T cells could be a promising treatment strategy for gastric cancer and potentially other CLDN18.2-positive tumors.
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ISSN:1460-2105
1460-2105
DOI:10.1093/jnci/djy134