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

## TL;DR

This review discusses current and emerging immunotherapy strategies for metastatic uveal melanoma, highlighting combination therapies and new targets to improve treatment outcomes.

## Contribution

The paper provides a meta-analytical comparison of immunotherapy regimens and identifies tebentafusp as a promising treatment for a specific genetic subset of patients.

## Key findings

- Combination immunotherapy with Ipilimumab, anti-PD-1 agents, and tebentafusp improves survival and response rates in metastatic uveal melanoma.
- Tebentafusp shows superior efficacy and safety in HLA-A*02:01-positive patients.
- Dendritic cell-based therapies and peptide vaccines show early promise in tumor-specific immune activation.

## 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.