Abstract
Simple SummaryImmune checkpoint inhibitors (ICIs) have revolutionized treatment of advanced melanoma and survival of melanoma patients has radically improved since. However, as durable responses after ICIs are only observed in 30–50% of melanoma patients, there is an unmet need to identify predictive biomarkers for response. This systematic review demonstrates the substantial number of publications that have studied a wide variety of possible biomarkers. Covering 177 publications that investigated 128 unique biomarkers, we provide an overview of all studied biomarkers in correlation with response or survival. We highlight blood, tumor and fecal biomarkers that were associated with response to ICIs in multiple studies. Of these, only T-cell inflamed gene expression profiling was predictive for response in a large clinical trial and validated in other studies, thus representing a promising biomarker for clinical practice. Large validation studies are warranted to confirm the predictive utility of other biomarkers, thereby further personalizing immunotherapy treatment.Immune checkpoint inhibitors (ICIs) have strongly improved the survival of melanoma patients. However, as durable response to ICIs are only seen in a minority, there is an unmet need to identify biomarkers that predict response. Therefore, we provide a systematic review that evaluates all biomarkers studied in association with outcomes of melanoma patients receiving ICIs. We searched Pubmed, COCHRANE Library, Embase, Emcare, and Web of Science for relevant articles that were published before June 2020 and studied blood, tumor, or fecal biomarkers that predicted response or survival in melanoma patients treated with ICIs. Of the 2536 identified reports, 177 were included in our review. Risk of bias was high in 40%, moderate in 50% and low in 10% of all studies. Biomarkers that correlated with response were myeloid-derived suppressor cells (MDSCs), circulating tumor cells (CTCs), CD8+ memory T-cells, T-cell receptor (TCR) diversity, tumor-infiltrating lymphocytes (TILs), gene expression profiling (GEP), and a favorable gut microbiome. This review shows that biomarkers for ICIs in melanoma patients are widely studied, but heterogeneity between studies is high, average sample sizes are low, and validation is often lacking. Future studies are needed to further investigate the predictive utility of some promising candidate biomarkers.
Highlights
Metastatic melanoma is a tumor with poor prognosis and the incidence will continue to rise in the years to come
We aimed to identify studies in advanced melanoma patients receiving immune checkpoint inhibitors (ICIs) that investigated the association between blood, tumor, and fecal biomarkers with outcomes
We found 24 reports that analyzed4 ofp1a9 ramet ment cohort as well as a validation cohort and 153 reports that only eoxmcluadrekde1r0s6 sitnudaiesdaenvde1l6o1pstmudeienstraelmsatinueddysuditaebsliegfnor. oIunr rmevoieswt. sCtruosdsireesfe,re5n5c–in7g0% of t itdieenntitfisedwaneortehemr 1e6nre.lIenvafnotrpmubalitciaotinonas,bwohuicthrraescueltwedains1o7n5 olyrigdineasl cpruibbliecadtioinnsftihvate studi we included in our review (Figure 1, Supplementary Material for complete reference list)
Summary
Metastatic melanoma is a tumor with poor prognosis and the incidence will continue to rise in the years to come. Since the introduction of novel therapeutic agents, such as immunotherapy with immune checkpoint inhibitors (ICIs) and targeted therapy, survival of patients with advanced melanoma has radically improved. Immune checkpoint inhibitors aim to unleash the compromised T-cells, thereby inducing an anti-tumor response [2]. Anti-CTLA-4 antibodies block T-cell inhibition, thereby promoting T-cell activation and the anti-tumor response. Response rates were lower than 20% and immune-related adverse events grade 3–4 were seen in approximately 15–45% of all patients [3]. Anti-PD-1 antibodies aim to prevent inhibitory signaling in activated effector T-cells by blocking their binding to PD-L1/2, resulting in functional Tcells that are possibly able to kill tumor cells. Grade 3–4 toxicity rates remain at 40% due to anti-CTLA-4 therapy [4,5,6]
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