Circulating Cytokines Predict Immune-Related Toxicity in Melanoma Patients Receiving Anti-PD-1–Based Immunotherapy

Abstract

Purpose: Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity. Experimental Design: The expression of 65 cytokines was profiled longitudinally in 98 patients with melanoma treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high-dose steroids. Results: Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at base-line (PRE) and early during treatment (EDT). The expression of these 11 cytokines was integrated into a single toxicity score, the CYTOX (cytokine toxicity) score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. The AUC for the CYTOX score in the validation cohort was 0.68 at PRE [95% confidence interval (CI), 0.51-0.84; P ¼ 0.037] and 0.70 at EDT (95% CI, 0.55-0.85; P ¼ 0.017) using ROC analysis. Conclusions: The CYTOX score is predictive of severe immune-related toxicity in patients with melanoma treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes proinflammatory cytokines such as IL1a, IL2, and IFNa2, may help in the early management of severe, potentially lifethreatening immune-related toxicity. See related commentary by Johnson and Balko, p. 1452

Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune‐checkpoint inhibitors

“…It is interesting that previous reports mentioned that early decrease of IL‐8 was related to favorable prognosis of malignant melanoma with anti‐PD‐1 therapy . Solid evidence supports a tumor‐promoting role of IL‐8 in several human cancers . However, the role of serum levels of IL‐8 in patients with autoimmune thyroid diseases remain unclear .…”

“…Fluorescence intensity (Fi) values were derived from the discovery assay and are in direct proportion to reflect the amount of proteins in the samples. Fi values were log 2 transformed for analysis …”

The impact of body composition parameters on severe toxicity of nivolumab

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The MNK1/2-eIF4E axis drives melanoma plasticity, progression, and resistance to immunotherapy

“…Such a peripheral cytokine/chemokine signature might have prognostic value to predict responders of combination therapy with MNK1/2 inhibitors and immune checkpoint blockade. Strikingly, although demonstrating a better anti-tumor response, the combination therapy led to a profound decrease in a subset of circulating cytokines that have been previously associated with immune-related adverse events due to immune checkpoint blockade (Figure S7G)86,87 . Furthermore, in contrast to the BRaf CA/+ /Pten lox/lox eIF4E WT mice, the BRaf CA/+ /Pten lox/lox eIF4E KI mice are sensitive to anti-PD-1 monotherapy,…”

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