Biomarkers for Clinical Benefit of Immune Checkpoint Inhibitor Treatment—A Review From the Melanoma Perspective and Beyond

Abstract

BackgroundImmune checkpoint inhibition (ICI) with anti-CTLA-4 and/or anti-PD-1 antibodies is standard treatment for metastatic melanoma. Anti-PD-1 (pembrolizumab, nivolumab) and anti-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for treatment of several other advanced malignancies, including non-small-cell lung cancer (NSCLC); renal cell, and urothelial carcinoma; head and neck cancer; gastric, hepatocellular, and Merkel-cell carcinoma; and classical Hodgkin lymphoma. In some of these malignancies approval was based on the detection of biomarkers such as PD-L1 expression or high microsatellite instability.MethodsWe review the current status of prognostic and predictive biomarkers used in ICI for melanoma and other malignancies. We include clinical, tissue, blood, and stool biomarkers, as well as imaging biomarkers.ResultsSeveral biomarkers have been studied in ICI for metastatic melanoma. In clinical practice, pre-treatment tumor burden measured by means of imaging and serum lactate dehydrogenase level is already being used to estimate the likelihood of effective ICI treatment. In peripheral blood, the number of different immune cell types, such as lymphocytes, neutrophils, and eosinophils, as well as different soluble factors, have been correlated with clinical outcome. For intra-tumoral biomarkers, expression of the PD-1 ligand PD-L1 has been found to be of some predictive value for anti-PD-1-directed therapy for NSCLC and melanoma. A high mutational load, particularly when accompanied by neoantigens, seems to facilitate immune response and correlates with patient survival for all entities treated by use of ICI. Tumor microenvironment also seems to be of major importance. Interestingly, even the gut microbiome has been found to correlate with response to ICI, most likely through immuno-stimulatory effects of distinct bacteria. New imaging biomarkers, e.g., for PET, and magnetic resonance imaging are also being investigated, and results suggest they will make early prediction of patient response possible.ConclusionSeveral promising results are available regarding possible biomarkers for response to ICI, which need to be validated in large clinical trials. A better understanding of how ICI works will enable the development of biomarkers that can predict the response of individual patients.

Correlation between cutaneous adverse events and prognosis in patients with melanoma treated with nivolumab: A single institutional retrospective study

“…To optimize use of ICI, namely achieving good clinical effects with few adverse effects, it is important to determine biomarkers. Several biomarkers have been described, including clinical characteristics, blood cell counts, laboratory findings and tumor characteristics . In the present study, several markers, including PS, M1c, the number of metastasized organs, serum LDH levels, NLR and PLR at baseline correlated with OS in univariate analysis, consistent with the findings of previous reports .…”

“…Several biomarkers have been described, including clinical characteristics, blood cell counts, laboratory findings and tumor characteristics . In the present study, several markers, including PS, M1c, the number of metastasized organs, serum LDH levels, NLR and PLR at baseline correlated with OS in univariate analysis, consistent with the findings of previous reports . LDH levels may indicate tumor burden that is released by growing tumor and are included in stage classification of the American Joint Committee on Cancer.…”

Role of medical imaging for immune checkpoint blockade therapy: From response assessment to prognosis prediction

“…First, tissue‐based biomarkers, such as PD‐L1 expression, tumor infiltrating lymphocytes, mutational or neoantigen burden, are often evaluated using invasive histopathological tests and demonstrate restricted capacity in capturing the spatial and temporal heterogeneity of tumors . Second, noninvasive blood‐based biomarkers, that is, the account of lymphocytes and other immune cells circulating, peripheral blood T cell subsets and liquid biopsy, cannot provide accurate information on the status of each individual tumor lesion . Given these unmet clinical needs, noninvasive imaging biomarkers that allow assessment of both tumor lesions and the surrounding microenvironment may serve as highly valuable complements to tissue and blood biomarkers …”

“…Of note, it is essential for radiologists to realize that increased 18 F‐FDG uptake is not specific for neoplasms regardless of its high sensitivity, because other pathological processes, including inflammatory reaction, can also show elevated glucose metabolism. In this setting, it is a great challenge for readers to distinguish tumor progression and metastases from inflammation on PET scans . Future efforts are warranted to solve this dilemma in 18 F‐FDG PET/CT.…”

“…In this setting, it is a great challenge for readers to distinguish tumor progression and metastases from inflammation on PET scans. 54,57,62 Future efforts are warranted to solve this dilemma in 18 F-FDG PET/CT.…”