Advances and Challenges in Immunotherapy for Metastatic Uveal Melanoma: Clinical Strategies and Emerging Targets

Abstract

Uveal melanoma (UM), the most common primary intraocular malignancy in adults, poses a unique clinical challenge due to its high propensity for liver metastasis and poor responsiveness to conventional therapies. Despite the expanding landscape of immunotherapy in oncology, progress in managing metastatic uveal melanoma (mUM) remains limited, and no universally accepted standard of care has been established. In this review, we examine the current state and evolving strategies in immunotherapy for mUM, focusing on immune checkpoint inhibitors (ICIs), T cell receptor (TCR)-engineered therapies, and tumor-targeted vaccines. We also present a meta-analytical comparison of clinical outcomes between ICI monotherapy and combination regimens, alongside the recently FDA-approved T cell engager tebentafusp. Our analysis indicates that the triple combination of Ipilimumab, anti-PD-1 agents, and tebentafusp significantly enhances objective response rates, disease control rates, 1-year overall survival rates, and median overall survival (mOS) compared to ICI monotherapy alone. However, this enhanced efficacy is accompanied by increased toxicity due to broader immune activation. In contrast, tebentafusp offers superior tumor specificity and a more favorable safety profile in HLA-A*02:01-positive patients, positioning it as a preferred therapeutic option for this genetically defined subset of UM. Additionally, early-phase studies involving dendritic cell-based immunotherapies and peptide vaccines has shown encouraging signs of tumor-specific immune activation, along with improved tolerability. Collectively, this review underscores the urgent need for more precise and effective immunotherapeutic approaches tailored to the unique biology of mUM.

Keywords: TCR-based therapy; Tebentafusp; checkpoint inhibitors; immunotherapy; metastatic uveal melanoma; vaccines.

Figure 2

Comparative efficacy of ICIs and tebentafusp in mUM. Bar graphs depict clinical outcomes in mUM patients treated with monotherapy anti-CTLA-4 (Ipilimumab), monotherapy anti-PD-1 (nivolumab or pembrolizumab), combination anti-PD-1 and anti-CTLA-4, and tebentafusp. The outcomes analyzed include: (A) objective response rate (ORR), defined as the percentage of patients achieving complete or partial responses; (B) disease control rate (DCR), calculated as the proportion of patients with complete response, partial response, or stable disease; (C) one-year overall survival rate (1-year OSR); and (D) median overall survival (mOS), measured in months. The analysis included a total of 530 patients treated with Ipilimumab [24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44], 636 patients treated with anti-PD-1 agents (nivolumab and/or pembrolizumab [38,39,40,43,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61], 595 patients treated with combination ICI therapy (anti-PD-1 + anti-CTLA-4) [40,49,64,65,66,67,68,69,70,71,72,73,74,75,76,77], and 397 patients treated with Tebentafusb [18,78,79,110] (see Supplemental Tables S1–S3 for study details). Data are presented as means ± standard error of the mean (SEM). Statistical significance is indicated as * p ≤ 0.05 and ** p ≤ 0.01.

Figure 1

Anatomical illustration demonstrates a primary uveal melanoma (brown mass) arising from the choroid layer of the eye. (Right panel) Immunohistochemical analysis showing CD8+ T cell infiltration (red punctate staining) within the tumor microenvironment.