1210 Enhancing the therapeutic efficacy of immune checkpoint inhibition and targeted therapy using anti-tumor antibodies in mouse melanoma

Abstract

Antitumor antibodies have made a great clinical impact in combination with chemotherapy, but these regimens do not capitalize on their potential to enhance tumor immunogenicity. Further, no antitumor antibodies have been developed for melanoma, despite evidence for high immunogenicity and immunotherapeutic responsiveness. Antitumor immunity is evident in primary and metastatic melanoma from the presence of high levels of TIL capable of recognizing melanoma-derived antigens, however, potent regulatory signals limit the effector immune responses. To enhance the vaccinal effects of antitumor antibodies while removing suppressive signals, we first tested the combination of antitumor antibodies (TA99; anti-TYRP1) with antibody-mediated depletion of Treg in B16 mouse melanoma. We found that depletion of Treg in combination with treatment with TA99 resulted in a significant reduction of tumor growth in both subcutaneous and metastatic models, associated with an increase in CD8+ T cells and a strong CD3+CD137+ infiltrate. Moreover, TA99 also enhanced the therapeutic efficacy of anti-PD-1 and anti-CTLA-4 antibodies, which was associated with a greater CD8+, NK1.1+ and dendritic cell infiltrate, suggestive of an increased antitumor immune response. Further, we found that MEK inhibitor (MEKi) could be used to increase the expression of melanosomal antigens and pigmentation in B16 melanoma cells. Treatment of BRAFWT B16 melanomas with a combination of TA99 and MEKi resulted in a synergistic reduction in tumor growth. Finally, treatment of YUMM melanoma (BRAFV600E) with TA99/MEKi resulted in the complete elimination of tumors in the majority of animals, and produced durable responses. Taken together, our findings suggest that MEKi induce an increased expression of tumor-associated antigens, and that combination with anti-tumor antibodies generated a more robust adaptive antitumor response sustained by immune checkpoint inhibition therapy in B16 melanoma.