Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer

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.

PSCA is a target of chimeric antigen receptor T cells in gastric cancer

“…All procedures were undertaken under the approval of the Institutional Animal Care and Use Committee of GIBH. NOD-SCID-IL2Rg −/−mice were generated as previously described [20]. To develop the cancer xenograft models, NSI mice aged from 6 to 10 weeks were used.…”

“…We then constructed a third-generation CAR using a humanized single-chain variable fragment (scFv) derived from a mouse anti-human PSCA antibody and a thirdgeneration lentivirus vector composed of a CD3ζ intracellular domain and two costimulatory domains, those of CD28 and DAP10, as previously described [20] ( Fig. 2a).…”

“…To determine whether anti-PSCA CAR-T cells could be activated by antigen-expressing tumor cells in a target-specific manner, we cultured anti-PSCA CAR-T cells and GFP-T cells with BGC-823 tumor cells at a 1:1 ratio. It has been reported that T cell activation and differentiation can be monitored based on changes in the expression of a series of surface biomarkers [20]. After coculture with target cells for 24 h, a T cell surface marker profile was detected by flow cytometry.…”

CAR-T “the living drugs”, immune checkpoint inhibitors, and precision medicine: a new era of cancer therapy

“…Several CAR-T cell products targeting B cell maturation antigen (BCMA) as well as CD19 are under active clinical trials for RR multiple myeloma [58][59][60]. Several biomarkers such as CLL-1, EGFR, NKG2D, and mesothelin are being targeted in CAR-T cell trials for leukemia and solid tumors [61][62][63][64][65][66]. Dual-target CAR-T cells and sequential or cocktail CAR-T cell trials have been shown to provide clinical benefits for highly refractory cancers [67].…”

A promising cancer diagnosis and treatment strategy: targeted cancer therapy and imaging based on antibody fragment

“…Currently, low immunogenicity and small volume of scFv have good prospects for cancer therapy. As an example, chimeric antigen receptor T cells comprising anti-mesothelin scFv can redirect T cells to inhibit the growth of gastric cancer [30].…”