Analysis of Cytokines in Serum and Bronchoalveolar Lavage Fluid in Patients with Immune-Checkpoint Inhibitor Associated Pneumonitis: a Parallel Cohort Study

Abstract

BackgroundImmune-checkpoint inhibitors (ICI) present a new treatment for malignancies by boosting the immune system. This has led to a variety of immune-related adverse events, including ICI-associated pneumonitis (ICIaP). Diagnosis thereof is often challenging, and its pathogenesis has not yet been fully understood. The aim of this parallel cohort study was to investigate cytokines in serum and bronchoalveolar lavage fluid (BALF) expressed in patients with ICI-associated pneumonitis compared to healthy individuals.MethodsFrom January 2018 until June 2019, 401 adult patients with various lung diseases were prospectively enrolled in a BALF- and serum biobank, called BALOTHEK. Of these, 12 patients were diagnosed with ICIaP (Pembrolizumab, Ipilimumab, or both, and Durvalumab) and included in this parallel cohort study. Additionally, 12 healthy subjects from the biobank served as matched control group. The following 11 cytokines were simultaneously analyzed in BALF and serum of each study participant: interferon gamma, tumor necrosis factor alpha, interleukin (IL) 1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12p70, IL-13 and IL-17A. This study was approved by the local ethic review committee (BASEC-ID 2017-02307 and 2018-01724).ResultsAbsolute number and percentage of lymphocytes in BALF of patients with ICIaP were significantly higher compared to control group. For the investigated cytokines in serum and BALF, a significant increase of IL-6 levels was shown for patients with ICIaP (p=0.044, adjusted for multiple comparisons). ConclusionCytokine profile assessed in BALF shows promising potential for facilitating diagnosis and understanding of pathophysiology of ICIaP. IL-6 may not only contribute to better understanding of pathophysiology but also herald therapeutic implications for Tocilizumab.

Insights into Potential Pathogenesis and Treatment Options for Immune-Checkpoint Inhibitor-Related Pneumonitis

“…Regarding ICI-pneumonitis, there have been cases where infliximab was effective [40,67]. However, the current recommendation for the use of infliximab is largely from colitis data and levels of TNF-α were not elevated in BALF from ICI-pneumonitis compared with healthy controls [68]. Further evidence is warranted.…”

“…Tocilizumab is an anti-IL-6 antibody with adequate efficacy and safety for rheumatoid arthritis [71]. Levels of IL-6 were elevated in BALF from ICI-pneumonitis compared with healthy controls (126.0 vs. 1.9 pg/mL p = 0.044) [68]. Recently, tocilizumab efficacy has been reported from a single center for patients with irAEs that were refractory to initial steroid therapy [72].…”