Inflammatory Cytokines and ctDNA Are Biomarkers for Progression in Advanced-Stage Melanoma Patients Receiving Checkpoint Inhibitors

Abstract

Purpose: Checkpoint inhibitors have significantly improved treatment of metastatic melanoma. However, 40–60% of patients do not respond to therapy, emphasizing the need for better predictive biomarkers for treatment response to immune checkpoint inhibitors. Prorammed death-ligand 1(PD-L1) expression in tumor cells is currently used as a predictive biomarker; however, it lacks specificity. Therefore, it is of utmost importance to identify other novel biomarkers that can predict treatment outcome. Experimental design: We studied a small cohort of 16 patients with advanced-stage melanoma treated with first-line checkpoint inhibitors. Plasma samples were collected prior to treatment initiation and continuously during the first year of treatment. Circulating tumor DNA (ctDNA) level and the expression of ten inflammatory cytokines were analyzed. Results: We found that the ctDNA-level in a blood sample collected after 6–8 weeks of therapy is predictive for response to checkpoint inhibitors. Patients with undetectable ctDNA had significantly longer progression-free survival (PFS) compared with patients with detectable ctDNA (median 26.3 vs. 2.1 months, p = 0.006). In parallel, we identified that high levels of the cytokines monocyte chemoattractant protein 1 (MCP1) and tumor necrosis factor α(TNFα) in baseline blood samples were significantly associated with longer PFS compared to low level of these cytokines (median not reached vs. 8.2 months p = 0.0008). Conclusions: These findings suggest that the levels of ctDNA, MCP1, and TNFα in baseline and early follow-up samples can predict disease progression in metastatic melanoma patients treated with checkpoint inhibitors. Potentially, these minimally invasive biomarkers may identify responders from non-responders.

Prognostic Value of Pretreatment Neutrophil-to-Lymphocyte Ratio in HER2-Positive Metastatic Breast Cancer

“…Analysis of ctDNA has proven to be useful not only for examining the genomic status of tumors but also for shedding light on other aspects of the disease, including the immune status. Pedersen et al [ 39 ] reported that the baseline ctDNA level was closely related to the therapeutic effect of immune checkpoint inhibitors in patients with metastatic melanoma. DNA can stimulate the immune response via regulation of IFN and other proinflammatory mediators in immune cells in a manner dependent on structure and sequence (REFS), and immune cell activation can be observed with DNA alone or in complex with other molecules [ 40 ].…”

Gut microbiota diversity and composition in predicting immunotherapy response and immunotherapy-related colitis in melanoma patients: A systematic review

“…Additionally, more studies correlating metagenomic and metatranscriptomic data of GM to outcomes of melanoma patients on immunotherapy ought to be performed as the functional capacity may be more important rather than individual GM family/order/species. In addition, we eagerly await the outcome of multiple large-scale RCTs involving FMT in the context of ICB-refractory melanoma such as NCT04577729 and NCT04988841 (PICASSO) (ClinicalTrails.gov).We foresee that together with other promising biomarkers, GM composition and diversity will be integrated into a multiparameter model to accurately predict which subset of melanoma patients are likely to respond to ICB[ 10 , 11 , 47 ].…”

Correlating Radiomic Features of Heterogeneity on CT with Circulating Tumor DNA in Metastatic Melanoma

“…Alterations in ctDNA have been reported to provide earlier markers of response to therapy than morphological changes in tumor size [33,34], and if individual mutations are unique to an individual metastasis, it may be possible to track the progress of individual metastases over time, analogous to the lesion-specific information provided by noninvasively imaging of a metastasis during treatment [4,35]. A recent study in metastatic melanoma reported that ctDNA levels at baseline and early follow-up can predict disease progression in patients treated with checkpoint inhibitors [36]. A further study showed that baseline ctDNA detection was associated with poor prognosis in metastatic BRAF or NRAS-mutated melanoma patients [37].…”