Engineered adoptive T cell therapy prolongs survival in a preclinical model of advanced stage ovarian cancer [Human]

Purpose: Adoptive T cell therapy using high affinity T cell receptors (TCRs) 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 anti-tumor 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. Experimental Design: We used deep transcriptome profiling and immunohistochemical 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 stage 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. Results: Immunohistochemistry and gene expression profiling revealed striking similarities between tumors, including processing/presentation of similar candidate target antigens, suppressive immune cell infiltration, and expression of molecules that inhibit T cell function. Engineered T cells infiltrated mouse tumors but became progressively dysfunctional and failed to persist within tumors. 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. Conclusions: Treatment with engineered T cells may have clinical applicability in patients with advanced-stage HGSOC. Matched normal tissue, primary ovarian tumor, and metastatic tumor samples from untreated patients were analyzed.