Serum cytokines predict efficacy and toxicity, but are not useful for disease monitoring in lung cancer treated with PD-(L)1 inhibitors

Abstract

IntroductionPD-(L)1 inhibitors (IO) have improved the prognosis of non-small-cell lung cancer (NSCLC), but more reliable predictors of efficacy and immune-related adverse events (irAE) are urgently needed. Cytokines are important effector molecules of the immune system, whose potential clinical utility as biomarkers remains unclear.MethodsSerum samples from patients with advanced NSCLC receiving IO either alone in the first (1L, n=46) and subsequent lines (n=50), or combined with chemotherapy (ICT, n=108) were analyzed along with age-matched healthy controls (n=15) at baseline, after 1 and 4 therapy cycles, and at disease progression (PD). Patients were stratified in rapid progressors (RP, progression-free survival [PFS] <120 days), and long-term responders (LR, PFS >200 days). Cytometric bead arrays were used for high-throughput quantification of 20 cytokines and other promising serum markers based on extensive search of the current literature.ResultsUntreated NSCLC patients had increased levels of various cytokines and chemokines, like IL-6, IL-8, IL-10, CCL5, G-CSF, ICAM-1, TNF-RI and VEGF (fold change [FC]=1.4-261, p=0.026-9x10-7) compared to age-matched controls, many of which fell under ICT (FC=0.2-0.6, p=0.014-0.002), but not under IO monotherapy. Lower baseline levels of TNF-RI were associated with longer PFS (hazard ratio [HR]= 0.42-0.54; p=0.014-0.009) and overall survival (HR=0.28-0.34, p=0.004-0.001) after both ICT and IO monotherapy. Development of irAE was associated with higher baseline levels of several cytokines, in particular of IL-1β and angiogenin (FC=7-9, p=0.009-0.0002). In contrast, changes under treatment were very subtle, there were no serum correlates of radiologic PD, and no association between dynamic changes in cytokine concentrations and clinical outcome. No relationship was noted between the patients’ serologic CMV status and serum cytokine levels.ConclusionsUntreated NSCLC is characterized by increased blood levels of several pro-inflammatory and angiogenic effectors, which decrease under ICT. Baseline serum cytokine levels could be exploited for improved prediction of subsequent IO benefit (in particular TNF-RI) and development of irAE (e.g. IL-1β or angiogenin), but they are not suitable for longitudinal disease monitoring. The potential utility of IL-1/IL-1β inhibitors in the management and/or prevention of irAE in NSCLC warrants investigation.

Predictive value of peripheral blood biomarkers in patients with non-small-cell lung cancer responding to anti-PD-1-based treatment

“…We found that serum cytokines are unsuitable for disease monitoring, because the dynamic changes of cytokine levels may be affected by multiple factors including different treatments such as chemotherapy, the immune status of the patient, or treatment-related side effects. This aligns with previous findings that baseline serum cytokine levels could be used to predict the benefits of immunotherapy, but they are unsuitable for longitudinal disease monitoring [ 22 ].…”

Integrated circulating tumour DNA and cytokine analysis for therapy monitoring of ALK-rearranged lung adenocarcinoma

“…We previously reported that serum IL-6, IL-8, and IL-10 levels are elevated in metastatic non-ALK NSCLC compared to healthy controls [ 22 ]. By integrating these data with the results of the current work, we also observed that ALK + NSCLC patients that were treatment naive or at therapy baseline have significantly elevated serum IL-6, IL-8 and IL-10 levels compared to healthy controls (Supplementary Fig.…”

“…1b ). Published evidence of the serum biomarker potential of all 8 cytokines in NSCLC is available [ 22 ]. IFN-γ initiates antitumor processes by activating JAK-STAT signalling, and the transcription of IFN-γ-inducible genes resulting in cell-cycle arrest and apoptosis [ 23 ].…”

“…Serum concentration analysis was performed using the Fireplex Analysis Workbench version 2.2.274-ext. Quantification of serum levels for IL-6, IL-8 and IL-10 in healthy controls and non-ALK NSCLC patients was performed within another study as published before [ 22 ].…”

Pulmonary toxicity of immune checkpoint immunotherapy

“…For example, in a discovery cohort of 58 patients with melanoma, samples taken at baseline and at the time of toxicity identified 11 signature cytokines (including granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, fractalkine, basic fibroblast growth factor-2, IFN-α2, IL-12p70, IL-1a, IL-1β, IL-1 receptor agonist, IL-2, and IL-13) that strongly correlated with the development of severe irAEs, including two cases of pneumonitis ( 100 ). Another study looking specifically at 204 patients with NSCLC, of which 43 developed irAEs, found a similar proinflammatory increase in IL-1β cytokine but also elevations in IL-5, IL-8, IL-10, IL-12p70, and granzyme A and decreased G-CSF as predictors for irAEs that included pneumonitis (5 of a total of 43) ( 101 ). IL-5, IL-8, and IL-12p70 are considered proinflammatory cytokines ( 102 – 104 ).…”