Bispecific antibodies enhance tumor-infiltrating T cell cytotoxicity against autologous HER-2-expressing high-grade ovarian tumors

Epithelial ovarian cancer displays the highest mortality of all gynecological tumors. A relapse of the disease even after successful surgical treatment is a significant problem. Resistance against the current platinum-based chemotherapeutic standard regime requires a detailed ex vivo immune profiling of tumor-infiltrating cells and the development of new therapeutic strategies. In this study, we phenotypically and functionally characterize tumor cells and autologous tumor-derived alpha beta and gamma delta T lymphocyte subsets. Tumor-infiltrating (TIL) and tumor-ascites lymphocytes (TAL) were ex vivo isolated out of tumor tissue and ascites, respectively, from high-grade ovarian carcinoma patients (FIGO-stage IIIa-IV). We observed an increased gamma delta T cell percentage in ascites compared to tumor-tissue and blood of these patients, whereas CD8(+) alpha beta T cells were increased within TAL and TIL. The number of V delta 1 and non-V delta 1/V delta 2-expressing gamma delta T cells was increased in the ascites and in the tumor tissue compared to the blood of the same donors. Commonly in PBL, the V gamma 9 chain of the gamma delta T cell receptor is usually associated exclusively with the V delta 2 chain. Interestingly, we detected V delta 1 and non-V delta 1/V delta 2 T cells co-expressing V gamma 9, which is so far not described for TAL and TIL. Importantly, our data demonstrated an expression of human epidermal growth factor receptor (HER)-2 on high-grade ovarian tumors, which can serve as an efficient tumor antigen to target CD3 TIL or selectively V gamma 9-expressing gamma delta T cells by bispecific antibodies (bsAbs) to ovarian cancer cells. Our bsAbs efficiently enhance cytotoxicity of TIL and TAL against autologous HER-2-expressing ovarian cells.