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Mesothelin-Specific CAR T Cells Target Ovarian Cancer
Karolinska Inst, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden; Port Said Univ, Egypt.ORCID iD: 0000-0002-0463-1518
Karolinska Inst, Sweden.
Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
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2021 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 81, no 11, p. 3022-3035Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH , 2021. Vol. 81, no 11, p. 3022-3035
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-176850DOI: 10.1158/0008-5472.CAN-20-2701ISI: 000659297500021PubMedID: 33795251OAI: oai:DiVA.org:liu-176850DiVA, id: diva2:1570993
Note

Funding Agencies|Karolinska Institutet FoundationKarolinska Institutet [2018-02344]; CancerfondenSwedish Cancer Society [19 0359 Pj 01 H9, 19 0002 FE, 2018/858]; VetenskapsradetSwedish Research Council [2019-01541]; Swedish Childhood Cancer FoundationEuropean Commission [PR2017-0083]; Radiumhemmets research funding [181201, 161082]; Clas Groschinskys Minnesfond [M18224]

Available from: 2021-06-22 Created: 2021-06-22 Last updated: 2022-03-25

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