IL 15 enhances preclinical efficacy of anti-core 1 O-glycans monoclonal antibody NEO-201 against human endometrial and ovarian cancer

Background: Resistance of gynecological cancers to immunotherapy is due to their ability to impair the cytotoxic activity of immune cells. One strategy to overcome this resistance is the combination of different types of immunotherapies with different mechanisms of action and different targets. The disruption of O-glycosylation pathway in ovarian and endometrial cancer is associated with cancer growth, metastasis, and poor prognosis. Methods: In this study we treated in vitro endometrial and ovarian human cancer cell lines with the combination of the monoclonal antibody (mAb) NEO-201 and IL-15 to overcome the resistance of gynecological cancers to immunotherapy. The combination was also used in vivo to treat mice bearing human ovarian cancer. NEO-201 is a humanized IgG1 mAb that binds to core 1 and/or extended core 1 O-glycans expressed by human cancer cells (including different ovarian cancer subtypes), as well as non-cancerous CD15⁺ granulocytes and immunosuppressive cells. NEO-201 can mediate the killing of its target cells through different mechanisms of action, including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). One strategy to enhance ADCC mediated by mAbs is to boost natural killer (NK) cells with IL-15. A previous study showed that IL-15 superagonist complex (N-803) enhanced ADCC activity mediated by NEO-201 in vitro against several human carcinoma cells, by modulating NK cells activation and cytotoxicity. Results: In this study we demonstrated that IL-15 enhanced ADCC mediated by NEO-201 in vitro against human endometrial and ovarian cancer cell lines expressing NEO-201 target antigen, and that the combination of IL-15 and NEO-201, using purified human NK cells as effectors, had a modest effect in prolonging the survival of mice bearing human ovarian cancer, compared to IL-15 or NEO-201 alone. Conclusions: The ability of IL-15 to enhance NEO-201 efficacy, with NK cells as effectors, supports the hypothesis of combining NEO-201 and IL-15 with NK cell therapy (i.e. IL-15-secreting CAR-NK cells with a longer IL-15 in vivo half-life and stronger NK activity) for the treatment of gynecological cancers expressing O-glycans recognized by NEO-201.