Serum cytokines as a biomarker for immune checkpoint inhibitor toxicity in patients with pleural mesothelioma

Our plain-English summary of Serum cytokines as a biomarker for immune checkpoint inhibitor toxicity in patients with pleural mesothelioma, by S.J. Farooqi, Z. Zhao, Å.K. Öjlert, et al (Frontiers in Immunology, 2024).

The study

• Authors: S.J. Farooqi, Z. Zhao, Å.K. Öjlert, S. Thunold, H.V. Juul, M.M. Bjaanæs, H. Horndalsveen, H.M.G. Nymoen, Å. Helland, V.D. Haakensen
• Journal: Frontiers in Immunology
• Published: 2024;15:1480183
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Pleural mesothelioma (PM) is a rare cancer with a dismal prognosis. Dual immune checkpoint inhibitors have improved overall survival, but the rate of immune-related adverse events (irAEs) is high. Serum cytokines reflect systemic immune reactions and may serve as biomarkers for irAEs.

Patients And Methods: Patients with pleural mesothelioma treated with nivolumab and ipilimumab with or without UV1 vaccine in the NIPU study were included. Serum cytokine levels were measured by Bio-Plex Pro Human Cytokine Screening 48-Plex Panel Assay. Correlations between cytokine levels and irAEs were analyzed by generalized linear mixed models to identify potential diagnostic and predictive biomarkers.

Results: Higher levels of MIG, eotaxin, MIP-1α, IP-10, TNF-α, MIP-1β, IL-4, MIF, IL-16, IL-2RA, SCGF.β and PDFG-BB at baseline are associated with increased risk of developing one or more irAEs. In particular, higher baseline levels of MIG are positively associated with thyroiditis and hypophysitis, and elevated levels of IP-10 and MIG to dermatitis. During the course of treatment, higher levels of MIG, eotaxin, MIF, TNF-α, MIP-1β, IL-4 and IL-16 are associated with an ongoing irAE. We found both predictive and diagnostic value of MIF with fatigue and of eotaxin with both colitis and pneumonitis. Higher levels of CTACK is associated with a lower risk of developing hepatitis, both before and after treatment.

Conclusions: Elevated levels of certain cytokines, both before and after onset of treatment, correlate with specific irAEs in PM patients receiving ICIs. These cytokines may be used as biomarkers to predict and detect irAES.

Copyright © 2024 Farooqi, Zhao, Öjlert, Thunold, Juul, Bjaanæs, Horndalsveen, Nymoen, Helland and Haakensen.

In plain English

This study measured immune signaling proteins called cytokines in the blood of people with pleural mesothelioma. The patients were in a trial (NIPU) of the immunotherapy drugs nivolumab and ipilimumab, given with or without the UV1 vaccine. The article does not study asbestos exposure. The authors analyzed samples from 74 of the trial's 118 patients. Some were picked at random and others were added because they had treatment side effects. The authors then compared cytokine levels with immune-related side effects. Of the 74 patients, 65 (88%) had such side effects, 121 in total, and none were grade 4 or 5. Higher levels of 13 cytokines before treatment were associated with at least one side effect. Rises in seven cytokines during treatment were associated with a side effect happening at that time. For example, MIG was linked to thyroiditis, hypophysitis and dermatitis, MIF to fatigue, and eotaxin to colitis and pneumonitis. Higher CTACK was linked to less hepatitis. The authors concluded these cytokines may serve as biomarkers but need checking in larger groups. They noted possible selection bias and small numbers for rarer side effects.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Biomarker study using stored blood (serum) samples from patients in a randomized, multi-center, open-label trial (the NIPU study), analyzed with generalized linear mixed models (glmmLasso)
• Who was studied: 74 patients with inoperable pleural mesothelioma, selected from 118 patients in the multi-center NIPU trial: 34 in the arm with UV1 vaccine and 40 in the arm without. 27 were randomly selected; 47 more were added with a focus on patients who had side effects. Data cut-offs were February 2022 and December 2022. Trial sites are not listed in the article.
• Exposure: No asbestos exposure was studied. The exposure was treatment with nivolumab and ipilimumab, with or without the UV1 telomerase vaccine. 26 of 48 measured cytokines remained after out-of-range data were excluded, and these were examined against 11 types of immune-related side effects.
• Main results:
  • 65 of the 74 analyzed patients (88%) had immune-related adverse events, with 121 events in total
  • No grade 4 or 5 immune-related adverse events occurred in the analyzed patients
  • Higher levels of 13 cytokines before treatment were each associated with at least one immune-related adverse event
  • During treatment, higher levels of MIG, eotaxin, MIF, TNF-a, MIP-1b, IL-4 and IL-16 were associated with at least one ongoing immune-related adverse event
  • High baseline MIG was associated with higher risk of arthralgia, colitis, hypophysitis, pancreatitis, thyroiditis and dermatitis
  • High baseline IP-10 was associated with higher risk of allergic reaction, hepatitis, pancreatitis and dermatitis
  • Hepatitis: higher CTACK levels during treatment were linked with less hepatitis (mean effect -0.23, SD 0.04). At baseline, CTACK showed a mean effect of -0.21 (SD 0.07).
  • MIF was positively associated with fatigue, both before and after treatment started
  • Higher eotaxin, both before and after the start of treatment, was associated with colitis and pneumonitis
  • No cytokines were found to be associated with nephritis
  • Prednisolone was linked to slight further increases in IL-4 (pneumonitis), GRO-a (hypophysitis) and CTACK (allergic reactions), and had no measurable impact on the other cytokines
• The authors' conclusion: The authors concluded that elevated baseline MIG predicts future development of multiple side effects, but has weak or no diagnostic value for ongoing ones. They concluded that these cytokines may serve as predictive and diagnostic biomarkers, and that validation in larger cohorts would be of interest.
• Limitations the authors state:
  • Missing time points for some patients limited the analysis of changes over time
  • Possible selection bias, because later sample batches focused on patients with side effects
  • Multiple side effects in the same patient were not analyzed together
  • Few patients had certain side effects (hypophysitis n = 4, pancreatitis n = 5, nephritis n = 4), which reduced statistical power
  • Few patients were available for the prednisolone analysis

Topics

Medical terms in this study, explained in our Lexicon: Cytokine, Biomarker, checkpoint inhibitors, Pleural Mesothelioma, Prognosis, Overall Survival, Immune-Related Adverse Events, Nivolumab (Opdivo).

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