Melanoma Immunotherapy: Next-Generation Biomarkers

The recent emergence of cancer immunotherapies initiated a significant shift in the clinical management of metastatic melanoma. Prior to 2011, melanoma patients only had palliative treatment solutions which offered little to no survival benefit. In 2018, with immunotherapy, melanoma patients can now contemplate durable or even complete remission. Treatment with novel immune checkpoint inhibitors, anti-cytotoxic T-lymphocyte protein 4 and anti-programmed cell death protein 1, clearly result in superior median and long-term survivals compared to standard chemotherapy; however, more than half of the patients do not respond to immune checkpoint blockade. Currently, clinicians do not have any effective way to stratify melanoma patients for immunotherapies. Research is now focusing on identifying biomarkers which could predict a patient’s response prior treatment initiation (or very early during treatment course), in order to maximize therapeutic efficacy, avoid unnecessary costs, and undesirable heavy side effects for the patient. Given the rapid developments in this field and the translational potential for some of the biomarkers, we will summarize the current state of biomarker research for immunotherapy in melanoma, with an emphasis on omics technologies such as next-generation sequencing and mass cytometry (CyTOF). Immunotherapy has revolutionized the management of metastatic melanoma. Prior to 2011, the median survival for metastatic melanoma was 9 months, compared to greater than 18 months in 2017 (1). Patients now benefit from novel immune checkpoint inhibitors (ICIs), anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1). From the latest survival data of the Checkmate 067 trial, progression-free survival (PFS) for ipilimumab is 2.9 months, for nivolumab 6.9 months, and for the combination of nivolumab and ipilimumab 11.5 months. Overall survival (OS) of the ipilimumab group was 19.9 and 37.6 months for the nivolumab group. Median OS was not reached in the combination nivolumab and ipilimumab group with a minimum follow-up time of 36 months (2–6). Although OS is extended, not all patients benefit from immunotherapy. Response rates for ipilimumab range from 11% to 19% (4, 5) and for pembrolizumab or nivolumab from 33% to 44% (2, 6, 7). These new ICIs clearly show superior median and long-term survivals compared to standard chemotherapy; however, more than half of the patients do not respond to immune checkpoint blockade. Currently, there are no clinically approved biomarkers to aid in patient selection in melanoma. In this review, we seek to delineate the current state of biomarker research for immunotherapy in melanoma, with an emphasis on omics technologies such as next-generation sequencing (NGS) and mass cytometry (CyTOF). Given the urgent clinical need for such biomarkers, we decided to focus on human studies only, which we think are more clinically relevant