Dendritic cell vaccination in metastatic uveal melanoma as compassionate treatment: Immunological and clinical responses.

Abstract

e21024 Background: Other than cutaneous melanoma, metastatic uveal melanoma (UM) is minimally responsive to checkpoint inhibitors. The prognosis remains very poor with mortality rates nearly unchanged over the last decades. The recently growing insight that immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of vaccines including dendritic cell (DC) vaccines. Methods: We vaccinated an UM patient in a compassionate use setting and assessed the immunological and clinical responses. Based on this experience we performed individual compassionate treatments in other UM patients using DC loaded by peptide pulsing and/or mRNA transfection (autologous tumor RNA or RNA coding for tumor antigens). Results: The first patient was vaccinated in 2013 after a liver metastasis was resected and checkpoint blockade with ipilimumab was started. In 2014 the patient showed progression in the liver. We continued DC vaccination in shorter intervals and adapted antigen loading (with mRNA coding for an individual GNAQ driver mutation) accompanied by a further cycle of ipilimumab. Therapy resulted in complete remission of liver metastases, but the patient developed new skin metastases. Again the loading of DC was adapted (peptides of passenger mutations predicted after Next-Generation Sequencing) and infusions with pembrolizumab were started. Pathology from some regressing lesions showed a massive T cell infiltration and in parallel GNAQ mutation-specific T cells could be found in the patient’s blood. Skin metastases regressed and the patient is now free of detectable tumor after 65 months. Immune monitoring in the patient’s blood showed a vaccine-induced functional T cell response against the QNAQ-driver mutation. Three of other four patients are also still alive, one in complete remission under DC vaccination in combination with pembrolizumab, two of them showing measurable disease, and one deceased disease related after 28 months, resulting in a median OS of the five patients of 36.4 months. Immune monitoring in one of those patients showed a CD4+ and CD8+ INF-gamma T cell response against the autologous tumor RNA vaccine. No grade 3 or 4 toxicity occurred. Conclusions: The observed prolonged median OS and the fact that 2/5 patients remain disease-free is definitely encouraging. Vaccination immunotherapy with antigen-laden DC is a potential therapeutic option for patients with metastatic uveal melanoma. Combinations with checkpoint inhibitors proved promising, and should be further evaluated in clinical trials.