Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer.
J Hematol Oncol
; 12(1): 18, 2019 02 18.
Article
em En
| MEDLINE
| ID: mdl-30777106
ABSTRACT
BACKGROUND:
Gastric cancer (GC) is a common cancer in Asia and currently lacks a targeted therapy approach. Mesothelin (MSLN) has been reported to be expressed in GC tissue and could be targeted by chimeric antigen receptor (CAR) T cells. Mesothelin targeting CAR-T has been reported in mesothelioma, lung cancer, breast cancer, and pancreas cancer. However, the feasibility of using anti-MSLN CAR T cells to treat GC remains to be studied.METHODS:
We verified MSLN expression in primary human GC tissues and GC cell lines and then redirected T cells with a CAR containing the MSLN scFv (single-chain variable fragment), CD3ζ, CD28, and DAP10 intracellular signaling domain (M28z10) to target MSLN. We evaluated the function of these CAR T cells in vitro in terms of cytotoxicity, cytokine secretion, and surface phenotype changes when they encountered MSLN+ GC cells. We also established four different xenograft GC mouse models to assess in vivo antitumor activity.RESULTS:
M28z10 T cells exhibited strong cytotoxicity and cytokine-secreting ability against GC cells in vitro. In addition, cell surface phenotyping suggested significant activation of M28z10 T cells upon target cell stimulation. M28z10 T cells induced GC regression in different xenograft mouse models and prolonged the survival of these mice compared with GFP-transduced T cells in the intraperitoneal and pulmonary metastatic GC models. Importantly, peritumoral delivery strategy can lead to improved CAR-T cells infiltration into tumor tissue and significantly suppress the growth of GC in a subcutaneous GC model.CONCLUSION:
These results demonstrate that M28z10 T cells possess strong antitumor activity and represent a promising therapeutic approach to GC.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Gástricas
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Linfócitos T
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Proteínas Ligadas por GPI
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Receptores de Antígenos Quiméricos
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Antígenos de Neoplasias
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article