Immunotherapies for the Treatment of Uveal Melanoma-History and Future

Abstract

Background: Uveal melanoma is the most common primary intraocular malignancy among adults. It is, nevertheless, a rare disease, with an incidence of approximately one case per 100,000 individuals per year in Europe. Approximately half of tumors will eventually metastasize, and the liver is the organ usually affected. No standard-of-care treatment exists for metastasized uveal melanoma. Chemotherapies or liver-directed treatments do not usually result in long-term tumor control. Immunotherapies are currently the most promising therapy option available.

Methods: We reviewed both relevant recent literature on PubMed concerning the treatment of uveal melanoma with immunotherapies, and currently investigated drugs on ClinicalTrials.gov. Our own experiences with immune checkpoint blockers are included in a case series of 20 patients.

Results: Because few clinical trials have been conducted for metastasized uveal melanoma, no definitive treatment strategy exists for this rare disease. The outcomes of most immunotherapies are poor, especially compared with cutaneous melanoma. However, encouraging results have been found for some very recently investigated agents such as the bispecific tebentafusp, for which a remarkably increased one-year overall survival rate, and similarly increased disease control rate, were observed in early phase studies.

Conclusions: The treatment of metastatic uveal melanoma remains challenging, and almost all patients still die from the disease. Long-term responses might be achievable by means of new immunological strategies. Patients should therefore be referred to large medical centers where they can take part in controlled clinical studies.

Keywords: IMCgp100; adoptive T-cell therapy; checkpoint inhibitors; dendritic-cell vaccination; immunotherapy; tebentafusp; uveal melanoma.

Figure 1

Stage-IV uveal melanoma patient with liver metastases shown in contrast-agent-enhanced computer tomography (CT) scans (A–D). Partial response of liver metastases under combined immune therapy with ipilimumab 3 mg/kg and nivolumab 1 mg/kg every three weeks. A and C show liver metastases before immune therapy. B and D show liver metastases in the same location (A corresponds to B, C corresponds to D) after three administration cycles. Arrows indicate metastases. With thanks to O. Sedlaczek, Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital.

Figure 2

Overview of best evidence to date for immunotherapeutic treatment in uveal melanoma compared to cutaneous melanoma [61].