Increased Soluble PD-1 Predicts Response to Nivolumab plus Ipilimumab in Melanoma

Abstract

Background: Checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, yielding long-term survival in a considerable proportion of the patients. Yet, 40–60% of patients do not achieve a long-term benefit from such therapy, emphasizing the urgent need to identify biomarkers that can predict response to immunotherapy and guide patients for the best possible treatment. Here, we exploited an unsupervised machine learning approach to identify potential inflammatory cytokine signatures from liquid biopsies, which could predict response to immunotherapy in melanoma. Methods: We studied a cohort of 77 patients diagnosed with unresectable advanced-stage melanoma undergoing treatment with first-line nivolumab plus ipilimumab or pembrolizumab. Baseline and on-treatment plasma samples were tested for levels of PD-1, PD-L1, IFNγ, IFNβ, CCL20, CXCL5, CXCL10, IL6, IL8, IL10, MCP1, and TNFα and analyzed by Uniform Manifold Approximation and Projection (UMAP) dimension reduction method and k-means clustering analysis. Results: Interestingly, using UMAP analysis, we found that treatment-induced cytokine changes measured as a ratio between baseline and on-treatment samples correlated significantly to progression-free survival (PFS). For patients treated with nivolumab plus ipilimumab we identified a group of patients with superior PFS that were characterized by significantly higher baseline-to-on-treatment increments of PD-1, PD-L1, IFNγ, IL10, CXCL10, and TNFα compared to patients with worse PFS. Particularly, a high PD-1 increment was a strong individual predictor for superior PFS (HR = 0.13; 95% CI 0.034–0.49; p = 0.0026). In contrast, decreasing levels of IFNγ and IL6 and increasing levels of CXCL5 were associated with superior PFS in the pembrolizumab group, although none of the cytokines were individually predictors for PFS. Conclusions: In short, our study demonstrates that a high increment of PD-1 is associated with superior PFS in advanced-stage melanoma patients treated with nivolumab plus ipilimumab. In contrast, decreasing levels of IFNγ and IL6, and increasing levels of CXCL5 are associated with response to pembrolizumab. These results suggest that using serial samples to monitor changes in cytokine levels early during treatment is informative for treatment response.

Soluble PD‐L1 predicts tumor response and immune‐related adverse events in patients with advanced melanoma treated with anti–PD‐1 antibodies

“…19 Moreover, Himuro et al 20 Another study showed that a high increment of sPD-1 is associated with superior survival in patients with advanced melanoma treated with nivolumab plus ipilimumab, although baseline sPD-L1 was not associated with the prognosis. 22 It remains largely unclear why these studies yielded different results although distinct cohorts (including different tumor type, tumor burden, metastatic status, and treatment method) in each study might contribute to this discrepancy. In our study, high sPD-L1 levels before anti-PD-1 antibody treatment also showed better prognosis, although posttreatment sPD-L1 or fluctuation of sPD-L1 levels were not associated with prognosis.…”

“…reported that patients with melanoma who have high levels of sPD‐L1 are prone to exhibit PD during ICI treatment (ipilimumab monotherapy or combination therapy of ipilimumab plus bevacizumab [anti–vascular endothelial growth factor antibody] or sargramostim [recombinant human granulocyte‐macrophage colony stimulating factor]). Another study showed that a high increment of sPD‐1 is associated with superior survival in patients with advanced melanoma treated with nivolumab plus ipilimumab, although baseline sPD‐L1 was not associated with the prognosis 22 …”

The combination of soluble forms of PD-1 and PD-L1 as a predictive marker of PD-1 blockade in patients with advanced cancers: a multicenter retrospective study

“…Another study reported that pretreatment sPD-1 levels were not related to either PFS or OS for advanced NSCLC patients treated with ICIs either alone or together with cytotoxic chemotherapy ( 31 ). In a study of patients with advanced melanoma, an increase in the sPD-1 concentration after the onset of treatment was a strong individual predictor of a better PFS for nivolumab plus ipilimumab, an antibody to cytotoxic T lymphocyte–associated protein–4 (CTLA-4), implicating sPD-1 in the activation of CD8 + T lymphocytes and the antitumor immune response ( 32 ). High sPD-1 levels might be a negative predictor for PD-1 blockade therapy if sPD-1 acts as a decoy for PD-1 antibodies and thereby attenuates their action in the TME.…”

Analysis of circulating tumor DNA during checkpoint inhibition in metastatic melanoma using a tumor-agnostic panel

“…For this purpose, we analyzed the ctDNA MAF in serial samples in all patients and compared it to treatment response (Figs. [4][5][6]. In patients with response to treatment, ctDNA was not detected at any time point in 5/11 patients.…”

“…Potential biomarkers include high PDL1 expression for anti-PD1/PDL1 therapies, and high tumor mutational burden (TMB), both now approved by the United States Food and Drug Administration (FDA) as an indication for using immunotherapy unrelated to diagnosis [ 2 ]. Other biomarkers have been reported as associated with immunotherapy response, including clonal TMB [ 3 ], an inflammation gene expression signature [ 4 ], and a signature based on soluble PD-1 [ 5 ]. Additionally, somatic mutations of specific genes in the cancer cells have been found to influence the tumor microenvironment and the ability of tumor cells to evade the immune system, and hereby confer immunotherapy resistance [ 6 ].…”