Abstract IA21: Translating immunotherapy from melanoma to other skin cancers

Abstract

Abstract The PD-1 pathway, including the immune cell receptor Programmed Cell Death 1 (PD-1) and its ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), mediates immunosuppression within the tumor microenvironment. Drugs designed to “release the brakes” on antitumor immunity by blocking PD-1 have demonstrated substantial and durable activity in patients with advanced unresectable melanoma, as well as those with resected melanomas having a high risk for postsurgical relapse. These findings supported FDA approvals for anti-PD-1 drugs in the adjuvant and advanced melanoma settings. Research in melanoma subtypes and other kinds of cancers has identified two tumor markers associated with the likelihood of anti-PD-1 response: PD-L1 protein expression and tumor mutational burden (TMB), reflecting neoantigen load. Cutaneous melanomas are often caused by UV irradiation, harbor high TMBs, and frequently express PD-L1. Other types of skin cancers caused by UV irradiation, such as squamous cell and basal cell carcinomas, harbor high TMBs, express PD-L1, and have shown sensitivity to anti-PD-1. Merkel cell carcinoma has a unique biology, since only ~20% of cases are caused by UV light (high TMB), while the remaining 80% are associated with the oncogenic Merkel cell polyomavirus (very low TMB). Interestingly, both varieties are highly responsive to PD-1 pathway blockade, indicating that a limited number of strong tumor antigens (viral antigens) can compensate for low TMB to elicit antitumor immunity and tumor rejection. Anti-PD-1 has shown promising activity in neoadjuvant (presurgical) trials in melanoma and Merkel cell carcinoma. Neoadjuvant trials afford the opportunity for in-depth tissue analysis, and a variety of tumor markers are under investigation for correlation with treatment outcomes. The continued interrogation of tumor markers potentially predictive of clinical outcomes is expected to further refine the risk:benefit profile for PD-1/PD-L1 antagonists in melanoma and other skin cancers. Future clinical investigations will focus on difficult-to-treat populations such as immunosuppressed patients, including solid organ transplant recipients and those with HIV infection, who are at increased risk to develop aggressive skin cancers. Supported by National Institutes of Health R01 CA142779, Bristol-Myers Squibb, Melanoma Research Alliance, Barney Foundation, Laverna Hahn Charitable Trust, and Moving for Melanoma of Delaware. Citation Format: Suzanne L. Topalian. Translating immunotherapy from melanoma to other skin cancers [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA21.