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

Our plain-English summary of Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer, by J. Lv, R. Zhao, D. Wu, et al (Journal of Hematology & Oncology, 2019).

The study

• Authors: J. Lv, R. Zhao, D. Wu, D. Zheng, Z. Wu, J. Shi, X. Wei, Q. Wu, Y. Long, S. Lin, S. Wang, Z. Wang, Y. Li, Y. Chen, Q. He, S. Chen, H. Yao, Z. Liu, Z. Tang, Y. Yao, D. Pei, P. Liu, X. Zhang, Z. Zhang, S. Cui, R. Chen, P. Li
• Journal: Journal of Hematology & Oncology
• Published: 2019;12(1):18
• Cited by: 103 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory and animal study testing whether mesothelin (MSLN) can serve as a target for chimeric antigen receptor (CAR) T cells in gastric cancer. The authors stained nine primary gastric cancer samples and reported robust MSLN expression in most of them compared with normal gastric tissue, and found that all four gastric cancer cell lines tested (BGC-823, AGS, KATO III, MKN-28) expressed MSLN, with higher levels in BGC-823 and MKN-28. T cells from healthy donors were engineered with a third-generation CAR (M28z10: MSLN scFv, CD28 transmembrane, CD3-zeta, plus CD28 and DAP10 costimulatory domains). In 18-hour killing assays, M28z10 T cells killed all four gastric cancer lines more than GFP-transduced T cells, while killing of MSLN-negative K562-GL cells was similar. After coculture with BGC-823-GL cells only, M28z10 T cells secreted more IL-2, IFN-gamma, GM-CSF and granzyme B than GFP T cells. In immunodeficient NSI mice, M28z10 T cells prolonged survival in intraperitoneal (P value = 0.0014) and pulmonary metastatic (P value = 0.0027) models, and peritumoral delivery improved tumour infiltration and growth suppression in subcutaneous models.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: human tissue and cell line analyses, in vitro CAR T cell assays, and xenograft mouse experiments
• Who was studied: Nine primary human gastric cancer samples plus normal gastric tissue, four human gastric cancer cell lines (BGC-823, AGS, KATO III, MKN-28), T cells from healthy donor PBMCs, and NOD-SCID IL2Rgamma-/- (NSI) mice aged 6-8 weeks, Guangzhou, China
• Exposure: Third-generation anti-mesothelin CAR T cells (M28z10) given at 5 x 10^6 cells intravenously or peritumorally, compared with GFP-transduced T cells
• Main results:
  • All four gastric cancer cell lines expressed MSLN, with higher levels in BGC-823 and MKN-28 than in AGS and KATO III
  • In 18-hour in vitro killing assays, M28z10 T cells were more cytotoxic than GFP T cells against the four gastric cancer lines, but not against MSLN-negative K562-GL cells
  • M28z10 T cells cocultured with BGC-823-GL cells (the only line tested for cytokines) secreted more IL-2, IFN-gamma, GM-CSF and granzyme B than GFP T cells
  • After stimulation with BGC-823 cells, M28z10 T cells showed activation and degranulation marker changes, with CD28 unchanged
  • In the intraperitoneal BGC-823-GL model, survival of M28z10-treated mice differed from controls with P value = 0.0014 (log-rank)
  • In the pulmonary metastatic (intravenously injected BGC-823-GL) model, survival differed with P value = 0.0027 (log-rank)
  • In subcutaneous models, peritumoral M28z10 T cells inhibited growth of both BGC-823 and MKN-28 tumours, whereas intravenous delivery had only modest effect on BGC-823 tumours
  • Tumour tissue of peritumorally treated mice contained more T cells than that of intravenously treated mice
• The authors' conclusion: The authors concluded that M28z10 T cells exerted antitumour activity against gastric cancer in vitro and in xenograft mouse models, and suggested mesothelin as a potential CAR T cell target for gastric cancer
• Limitations the authors state:
  • The authors reported xenogeneic graft versus host disease in some M28z10-treated mice, which they said reduced survival
  • The authors noted that intravenous treatment was only modestly effective against established subcutaneous BGC-823 tumours at the same dose
  • The authors stated that further CAR modifications remain to be tested to improve efficacy against large established gastric tumours

Topics

The National Library of Medicine indexes this study under subjects our site covers: Stomach cancer.

Medical terms in this study, explained in our Lexicon: Mesothelin, Stomach Cancer, Targeted Therapy, Mesothelioma, Lung Cancer, Cytokine, CAR-T Cell.

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