Exceptional response to combination ipilimumab and nivolumab in metastatic uveal melanoma: Insights from genomic analysis

Abstract

Uveal melanoma is the most common intraocular malignancy and has a poor prognosis compared to other melanoma subtypes with a median overall survival of 6–10 months. With immune checkpoint inhibitor therapy, either PD-1 inhibitor alone or combination ipilimumab/nivolumab (anti-CTLA-4/anti-PD-1), responses are rare and often not durable. We present a case report of a now 66-year-old woman with diffuse metastatic uveal melanoma previously treated with a combination of ipilimumab/nivolumab, followed by maintenance nivolumab. Almost complete resolution of all sites of metastatic disease was observed except for one liver metastasis which regressed partially on immunotherapy. Notably, the patient had a significantly elevated BMI and developed widespread vitiligo on treatment. Whole-genome and transcriptome analysis was performed on the residual liver biopsy and molecular markers that may have contributed to the exceptional response were investigated. Several alterations were observed in genes involved in T-cell responses. Estimates of tumour infiltrating immune cells indicated a high level of plasma cells compared to other uveal melanoma cases, a finding previously associated with indolent disease. The patient also carried several germline SNPs that may have contributed to her treatment response as well as widespread vitiligo. Whole-genome and transcriptome sequencing have provided insight into potential molecular underpinnings of an exceptional treatment response in a tumour type typically associated with poor prognosis. Immunological findings suggest a role for plasma cells in the tumour microenvironment. Elevated BMI and the development of vitiligo may be clinically relevant factors for predicting response to immune checkpoint inhibitor therapy, warranting further studies in patients with uveal melanoma.

Dermokine mutations contribute to epithelial-mesenchymal transition and advanced melanoma through ERK/MAPK pathways

“…Our pan-analyzing of melanoma samples by large-scale weighted gene co-expression network classified that during melanomagenesis, up-regulation of EMT- transcription factors contribute to vasculogenic mimicry (VM)-forming process, resulting in the resistance of anti-angiogenic and anti-vascular therapies for malignant tumor endothelial cells [ 7 , 8 ]. Therefore, transcriptome profiling of EMT/VM-mediated therapeutic resistance samples could be a valuable strategy for finding exceptional responders for the personalized melanoma therapy [ 9 , 10 ].…”

The Future of Checkpoint Inhibitors in Uveal Melanoma: A Narrative Review

“…Cases Reported to Benefit from Dual-Agent ICIs Significant efficacy has been reported in some rare cases [45]. Notably, both a 66-year-old woman [46] and a 53-year-old woman [47] with diffuse MUM treated with the combination of ipilimumab and nivolumab showed almost complete resolution of all metastatic sites. Genetic characteristics may play a role in therapeutic responses, as the former carried several germline single-nucleotide polymorphisms.…”

Dermokine mutations contribute to epithelial-mesenchymal transition and advanced melanoma through ERK/MAPK pathways

“…KY2019041). Written informed consent that conformed to the tenets of the Declaration of Helsinki (1983 Revision) [9,10] was obtained from all participants or their guardians for use of their clinical and pathology information, before the study. Additionally, all clinical assessments were processed according to the local Ethics Committee guidelines of the Pathology and Surgery Department at the A liated Hospital of Southwest Medical University, Sichuan, China.…”

“…This issue results in resisting malignant tumor endothelial cells to anti-angiogenic and antivascular therapies [7, 8]. Therefore, the transcriptome pro ling of the EMT/VM-mediated treatment-resistant samples could be a valuable strategy for nding exceptional responders to the personalized melanoma therapy [9,10].…”

“…This issue results in resisting malignant tumor endothelial cells to anti-angiogenic and antivascular therapies [7, 8]. Therefore, the transcriptome pro ling of the EMT/VM-mediated treatment-resistant samples could be a valuable strategy for nding exceptional responders to the personalized melanoma therapy [9,10].Recently, researchers tried to nd novel VM/EMT-targeted therapeutic genes that are differentially regulated during melanomagenesis. One of the identi ed genes was a recently-reported skin-speci c gene, phosphatidylserine-speci c phospholipase A1-alpha (PLA1A) and dermokine (DMKN) that contribute to melanomagenesis by triggering the EMT signaling pathway and VM formation [11,12].…”