Analysis of cytokines in serum and bronchoalveolar lavage fluid in patients with immune-checkpoint inhibitor-associated pneumonitis: a cross-sectional case–control study

Benedikt Kowalski,Urs C Steiner,Malcolm Kohler,Alan Valaperti,Pascal Bezel,Maya Vonow-Eisenring,Dieter Scholtze,Stephan Wieser,Daniel Franzen,Andrea Widmer

doi:10.1007/s00432-021-03750-z

Abstract

PurposeImmune-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 cross-sectional case–control study was to investigate cytokines in serum and bronchoalveolar lavage fluid (BALF) expressed in patients with ICIaP compared to controls consisting of healthy individuals, patients with lung cancer and patients with interstitial lung diseases (ILD) other than ICIaP.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) serving as case group. Subjects with one of three diagnosis groups from BALOTHEK, including lung cancer, ILD other than ICIaP, and healthy individuals, served as matched controls. 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 2017-02,307 and 2018-01,724).ResultsAbsolute number and percentage of lymphocytes in BALF of patients with ICIaP were significantly higher compared to control groups. For the investigated cytokines in BALF, a significant increase of IL-6 level was shown for patients with ICIaP compared to control groups (p = 0.031, 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.

Highlights

Both, chemo- and radiation therapy used to be the common approach for cancer treatment throughout decades
From the group with ICI-associated pneumonitis (ICIaP), seven subjects were treated for metastatic melanoma (58.3%) and five subjects for adenocarcinoma of the lung (41.7%)
Most patients in the interstitial lung diseases (ILD) group were diagnosed with pulmonary sarcoidosis (58.3%), whereas adenocarcinoma of the lung presented the majority in the lung cancer group (75.0%)

Summary

Introduction

Chemo- and radiation therapy used to be the common approach for cancer treatment throughout decades. Immune-checkpoint inhibitors (ICI) made of monoclonal antibodies (mAB) against receptors on T-lymphocytes have been introduced as a new therapeutic ideology in fighting cancer. Ipilimumab was the first ICI to be approved, representing a breakthrough in the treatment of metastatic melanoma (Hodi et al 2010). Clinical practice has changed (Dummer et al 2015) and new ICIs allowed treatment of various malignancies other than melanoma. Instead of repeated exposure to cytotoxic agents in traditional chemotherapy, ICIs boost the immune system by “inhibiting the inhibition” and, helping it to tackle neoplasia effectively (Kroschinsky et al 2017). The reported incidence for pneumonitis is 1.3–11% for ICI monotherapy (Abdel-Rahman and Fouad 2016) and 6.6% for combination therapy of Ipilimumab with Pembrolizumab or Nivolumab (Nishino et al 2016a)

Methods

Results

Conclusion