Abstract
Simple SummaryGlycoprotein 100 (Gp-100) is a protein highly expressed in melanoma tissue that has recently been effectively targeted by tebentafusp, a first-in-class bispecific protein of the immune-mobilizing monoclonal T cell receptors against cancer (ImmTACs) family. Recently, a randomized phase III trial reported an overall survival benefit for tebentafusp in patients with untreated metastatic uveal melanoma. Uveal melanoma is a rare neoplasm with poor prognosis in the metastatic setting. Unlike cutaneous melanoma, treatment with kinase inhibitors or immune checkpoint inhibitors is not effective. Glycoprotein 100 (Gp-100) is a protein highly expressed in melanocytes and melanoma that has recently been effectively targeted by tebentafusp, a first-in-class bispecific protein of the immune-mobilizing monoclonal T cell receptors against cancer (ImmTACs) family. Tebentafusp targets tumor cells that express a peptide of Gp-100 presented by HLA*A0201, creating an immune synapse that kills targeted tumor cells. Recently, a randomized phase III trial reported an overall survival benefit for tebentafusp in patients with untreated metastatic uveal melanoma. The aim of this comprehensive review is to summarize evidence of Gp-100 as a therapeutic target in melanoma, and the preclinical and clinical development of tebentafusp as a novel therapeutic strategy for patients with uveal melanoma.
Highlights
Uveal melanoma (UM) is a rare neoplasm that arises from uveal melanocytes [1] and represents 3–5% of all melanomas
Unlike cutaneous melanoma (CM), most UMs harbor a mutation in the Gαq pathway, mainly GNAQ and GNA11, both of which are α subunits of G proteins [1]
Uveal and cutaneous melanoma differ in their Glycoprotein 100 (Gp-100) tissue expression (80% of UM lesions express Gp-100 compared to 63% in CM) [11]
Summary
Uveal melanoma (UM) is a rare neoplasm that arises from uveal melanocytes [1] and represents 3–5% of all melanomas. Unlike cutaneous melanoma (CM), most UMs harbor a mutation in the Gαq pathway, mainly GNAQ and GNA11, both of which are α subunits of G proteins [1]. Another significant difference between UM and CM is the very low tumor mutational burden of the former, which may, to some extent, explain the lower efficacy of immunotherapy in UMs [3]. Chemotherapy was considered the standard of care for patients with stage IV disease, but the response rates are generally under 10% [5]. The median overall survival (OS) is still around 12 months [8]
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