The therapeutic outcomes of current strategies in melanoma treatment have greatly improved within the last decade. However, the persistent relatively low success rate of current standard-of-care strategies underscores the urgent need for improvement of these therapeutic approaches. The use of specific antitumor antibodies recently transformed the cancer therapeutics landscape with successes such as anti-HER2 in breast cancer, and anti-EGFR in HNSCC and colorectal cancer. However, antitumor antibodies have not been developed for the treatment of melanoma. Here, using mouse preclinical models of melanoma (both solid tumor and lung metastasis), we found that the therapeutic efficacy of the specific antitumor antibody TA99 (anti-TYRP1) is significantly enhanced by immune checkpoint blockade. This was associated with a greater CD8+, CD8+/Foxp3+, NK1.1+ and dendritic cell infiltrate, suggestive of an increased anti-tumor immune response. Further, MEK inhibition (MEKi) increased the expression of melanosomal antigens in B16 and YUMM mouse melanoma cell lines in vitro. We next combined TA99 and MEKi to treat B16 melanoma in vivo and observed a synergistic reduction in tumor growth. Treatment of mice bearing YUMM melanoma (BRAF mutant) with TA99/MEKi resulted in the complete elimination of tumors in the majority of animals, and produced durable responses. Moreover, we found a synergistic effect when B16 tumor-bearing mice were treated with TA99 combined with MEKi and immune checkpoint blockade (anti-PD1 and anti-CTLA4). Our findings suggest that MEKi induced an increased expression of tumor-associated antigens, which, in combination with antitumor antibodies, generated a robust adaptive antitumor response that was sustained by immune checkpoint inhibition therapy. These improved therapeutic effects of specific antitumor antibodies by current standard-of-care therapeutics have potential near-term translation to the clinic, in light of fully humanized anti-TYRP1 antibodies currently in clinical development.

Citation Format: Rolando Pérez-Lorenzo, Stephanie O. Erjavec, Raphael Clynes, Angela M. Christiano. Enhancing the efficacy of antitumor antibodies with immune checkpoint inhibitors and targeted therapy in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1845.