Journal
CANCER RESEARCH
Volume 81, Issue 11, Pages 3022-3035Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-2701
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Funding
- Karolinska Institutet Foundation [2018-02344]
- Cancerfonden [19 0359 Pj 01 H9, 19 0002 FE, 2018/858]
- Vetenskapsradet [2019-01541]
- Swedish Childhood Cancer Foundation [PR2017-0083]
- Radiumhemmets research funding [181201, 161082]
- Clas Groschinskys Minnesfond [M18224]
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The study demonstrates the therapeutic potential of MSLN-CAR T cells against ovarian cancer, despite challenges in achieving persistent tumor control. The findings highlight the importance of immune checkpoint pathways in limiting CAR T-cell persistence in the ovarian tumor microenvironment.
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 coin-hibitory 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. Significance: These findings demonstrate that MSLN-directed CAR T cells can provide antitumor immunity against ovarian cancer.
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