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Figure S4 from Mesothelin-Specific CAR T Cells Target Ovarian Cancer

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posted on 2023-03-31, 04:41 authored by Esther Schoutrop, Ibrahim El-Serafi, Thomas Poiret, Ying Zhao, Okan Gultekin, Rui He, Lidia Moyano-Galceran, Joseph W. Carlson, Kaisa Lehti, Moustapha Hassan, Isabelle Magalhaes, Jonas Mattsson

Figure S4

Funding

Karolinska Institutet

Cancerfonden

Vetenskapsrådet

Swedish Childhood Cancer Foundation

Radiumhemmets research funding

Clas Groschinskys Minnesfond

History

ARTICLE ABSTRACT

New therapeutic options for patients with ovarian cancer are urgently needed. Therefore, we evaluated the efficacy of two second-generation mesothelin (MSLN)-directed CAR T cells in orthotopic mouse models of ovarian cancer. Treatment with CAR T cells expressing an MSLN CAR construct including the CD28 domain (M28z) significantly prolonged survival, but no persistent tumor control was observed. Despite lower response rates, MSLN-4–1BB (MBBz) CAR T cells induced long-term remission in some SKOV3–bearing mice. Tumor-infiltrating M28z and MBBz CAR T cells upregulated PD-1 and LAG3 in an antigen-dependent manner while MSLN+ tumor cells expressed the corresponding ligands (PD-L1 and HLA-DR), demonstrating that coinhibitory pathways impede CAR T-cell persistence in the ovarian tumor microenvironment. Furthermore, profiling plasma soluble factors identified a cluster of M28z- and MBBz-treated mice characterized by elevated T-cell secreted factors that had increased survival, higher CD8+ T-cell tumor infiltration, less exhausted CAR T-cell phenotypes, and increased HLA-DR expression by tumor cells. Altogether, our study demonstrates the therapeutic potential of MSLN-CAR T cells to treat ovarian cancer. These findings demonstrate that MSLN-directed CAR T cells can provide antitumor immunity against ovarian cancer.

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