Adoptive T-cell therapy using high-affinity T-cell receptors (TCR) to target tumor antigens has potential for improving outcomes in high-grade serous ovarian cancer (HGSOC) patients. Ovarian tumors develop a hostile, multicomponent tumor microenvironment containing suppressive cells, inhibitory ligands, and soluble factors that facilitate evasion of antitumor immune responses. Developing and validating an immunocompetent mouse model of metastatic ovarian cancer that shares antigenic and immunosuppressive qualities of human disease would facilitate establishing effective T-cell therapies. We used deep transcriptome profiling and IHC analysis of human HGSOC tumors and disseminated mouse ID8VEGF tumors to compare immunologic features. We then evaluated the ability of CD8 T cells engineered to express a high-affinity TCR specific for mesothelin, an ovarian cancer antigen, to infiltrate advanced ID8VEGF murine ovarian tumors and control tumor growth. Human CD8 T cells engineered to target mesothelin were also evaluated for ability to kill HLA-A2 HGSOC lines. IHC and gene-expression profiling revealed striking similarities between tumors of both species, including processing/presentation of a leading candidate target antigen, suppressive immune cell infiltration, and expression of molecules that inhibit T-cell function. Engineered T cells targeting mesothelin infiltrated mouse tumors but became progressively dysfunctional and failed to persist. Treatment with repeated doses of T cells maintained functional activity, significantly prolonging survival of mice harboring late-stage disease at treatment onset. Human CD8 T cells engineered to target mesothelin were tumoricidal for three HGSOC lines. Treatment with engineered T cells may have clinical applicability in patients with advanced-stage HGSOC.
Bibliographical noteFunding Information:
This work was supported by the Chromosome Metabolism and Cancer Training Grant Program (T32 2T32CA009657-26A1; to K.G. Anderson), the Ovarian Cancer Research Alliance (to K.G. Anderson), a Solid Tumor Translational Research Award (to K.G. Anderson and P.D. Greenberg), the NIH NCI (CA018029 and CA033084; to P.D. Greenberg), the Leukemia & Lymphoma Society (to S.K. Oda), and a research agreement with Juno Therapeutics and the Parker Institute for Cancer Immunotherapy (to P.D. Greenberg). The authors thank Matthias Stephan for the ID8VEGF cell line; Sunni Farley, Robert Pierce, Savanh Chanthaphavong, Brian Johnson, and Megan Larmore for histopathology assistance; Frank Carbone for TCROTI construct development; Thomas Schmitt forMSLN-specific TCR development; Magdalia Suarez, Andrew Daman, Lara Kropp, and Rachel Perret for assistance with experiments; the Fred HutchinsonCancer Research Center Flow Cytometry Core for technical support; Deborah Banker for critical review of the manuscript; and all members of the Greenberg lab for thoughtful and critical discussion.*%blankline%*
©2019 American Association for Cancer Research.