Peripheral and local predictive immune signatures identified in a phase II trial of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV melanoma

Abstract

BackgroundCheckpoint blockade with ipilimumab provides long-term survival to a significant proportion of patients with metastatic melanoma. New approaches to increase survival and to predict which patients will benefit from treatment are needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP) to assess its safety, efficacy, and to search for peripheral and tumor-based predictive biomarkers.MethodsThirty patients with untreated unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse events (AEs) were monitored and response to treatment was evaluated. Tumor tissue and peripheral blood were collected at specified time points to characterize tumor immune markers by immunohistochemistry and systemic immune activity by multiplex assays and flow cytometry.ResultsEighty three percent of patients received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed. Best Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%, respectively. Median overall survival was 16.2 months. Response to treatment was positively correlated with a higher tumor CD3+ infiltrate (immune score) at baseline. NRAS and BRAF mutations were less frequent in patients who experienced clinical benefit. Assessment of peripheral blood revealed that non-responders had elevated baseline levels of CXCL8 and CCL4, and a higher proportion of circulating late differentiated B cells. Pre-existing high levels of chemokines (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly associated with worse patient overall survival. Elevated proportions of circulating CD8+/PD-1+ T cells during treatment were associated with worse survival.ConclusionsThe combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment. A pre-existing systemic inflammatory state characterized by elevation of selected chemokines and advanced B cell differentiation, was strongly associated with poor patient outcomes, revealing potential predictive circulating biomarkers.Trial registration Clinicaltrials.gov, NCT01676649, registered on August 29, 2012.Electronic supplementary materialThe online version of this article (10.1186/s40425-017-0290-x) contains supplementary material, which is available to authorized users.

Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers

“…The favorable and unfavorable roles of chemokines as prognostic factors in different types of cancers are summarized in Table 2. Interestingly, high levels of multiple chemokines were reported to be strongly associated with worse patient OS in several clinical trials [217][218][219]. In order to identify and validate multiple chemokines as promising and predictive tumor-based biomarkers for patient outcomes, further investigations in various clinical trials of anticancer treatments are necessary.…”

In-depth plasma proteomics reveals increase in circulating PD-1 during anti-PD-1 immunotherapy in patients with metastatic cutaneous melanoma

“…11 21 Altogether, some of these findings coincide with previous reports on the involvement of immunological proteins in antitumor response to CM. [22][23][24][25][26][27][28] Protein plasma levels can predict PFs To detect potential predictive biomarkers, we also analyzed the association between pre-trm plasma protein levels and PFS. No clinical variables were associated with PFS in the HiRIEF LC-MS/MS-analyzed subgroup of anti-PD-1 treatment cohort (n=13); therefore we performed univariate analyses, which showed associations between protein pre-trm plasma levels of 109 proteins and PFS in this cohort (p<0.05, no FDR; online supplementary table S8, additional file 2).…”

Simultaneous inhibition of CXCR1/2, TGF-β, and PD-L1 remodels the tumor and its microenvironment to drive antitumor immunity

“…12 38 42 Pretreatment serum IL-8 levels have also been shown in patients with melanoma to correlate with responses to treatment with the checkpoint inhibitor ipilimumab and chemotherapy, with high levels correlating with failure to treatment. 43 Blockade of IL-8 signaling may be achieved by direct neutralization of IL-8 or via inhibition of its receptors. Previously, our group showed that neutralization of IL-8 via a monoclonal anti-IL-8 in vitro and in vivo was able to revert mesenchymal features in claudin-low, triple negative tumor models, resulting in enhanced immune-mediated lysis with NK and antigen-specific T cells in vitro, and reduced tumor infiltration with G-MDSC in vivo.…”