Breakthrough immunotherapy data presented at ESMO 2025 is offering new hope for patients with metastatic uveal melanoma, a rare and historically treatment-resistant eye cancer. In a recent melanoma series featured on Medscape, Teresa Amaral, MD, reviewed compelling results from a phase 1 clinical trial investigating anzutresgene autoleucel (anzu-cel), a PRAME-directed T-cell receptor (TCR) therapy.
Uveal melanoma is considered a “cold tumor,” meaning it typically lacks immune cell infiltration and responds poorly to traditional immunotherapies that are effective in cutaneous melanoma. Current systemic options remain limited, with tebentafusp and liver-directed melphalan-based therapies offering modest benefit for select patients. Unfortunately, most individuals diagnosed with uveal melanoma ultimately develop metastatic disease—most often to the liver—where outcomes have historically been poor.
The anzu-cel trial set out to answer a critical question: can a highly targeted TCR therapy overcome immune resistance in uveal melanoma by focusing on a strongly expressed tumor antigen? PRAME (Preferentially Expressed Antigen in Melanoma) is present in a large proportion of uveal melanomas and other cancers, making it an attractive therapeutic target. Anzu-cel uses genetically engineered T cells designed to recognize PRAME-derived peptides presented on tumor cells via the HLA-A*02:01 complex.
In this phase 1 study, patients with previously treated metastatic uveal melanoma underwent leukapheresis, lymphodepletion, and a single infusion of anzu-cel, followed by optional low-dose interleukin-2. Of the 16 patients enrolled, the majority had liver metastases and had already received local and systemic therapies.
The results were striking. Investigators reported an overall response rate of 67%, with 10 of 15 evaluable patients responding—an unprecedented outcome in this disease setting. Responses appeared durable, with median overall survival not yet reached. At 12 months, overall survival was 71%, and median progression-free survival was 8.5 months. Importantly, the therapy demonstrated activity in patients with liver metastases, a major clinical challenge in metastatic uveal melanoma.
Toxicities were largely manageable and primarily related to lymphodepletion, with no grade 5 events reported and only low-grade cytokine release syndrome observed. While the therapy’s HLA-A*02:01 restriction limits eligibility and raises equity concerns, these findings represent a major step forward and support ongoing phase 2 trials.