Abstract 5527: Serum proteomic scores for understanding the mechanisms of immune-related adverse events (irAEs) in non-small cell lung cancer
Authors: Davis Andrew A. , Park Jonghanne , Kim Leeseul , Gim Gahyun , Iams Wade T. , Oh Michael S. , Lentz Robert W. , Roder Heinrich , Roder Joanna , Asmellash Senait , Net Lelia , Grigorieva Julia , Mohindra Nisha , Villaflor Victoria , Chae Young Kwang 
Published: September 2020

Abstract
Background:
Understanding of biological processes associated with irAEs for patients treated with immune checkpoint inhibitors (ICI) is limited. We used serum-based, proteomic scores at baseline and after treatment initiation to explore mechanisms of irAEs for patients with non-small cell lung cancer (NSCLC) treated with ICI.
Methods:
Under an ongoing clinical protocol, 43 patients with advanced NSCLC were consented and serum samples were prospectively collected at two timepoints: baseline and approximately 3 weeks after treatment initiation with ICI (median 22 [IQR, 21 - 26] days). Samples were analyzed, blinded to clinical data, using MALDI-ToF mass spectrometry. Protein Set Enrichment Analysis (PSEA) approach applied to mass-spectral data was used to assign biological scores characterizing activation of 10 processes of interest (e.g., Type 1 immunity, complement, interferon (IFN)-gamma). irAEs after initiation of ICI with or without chemotherapy were classified per standard definitions. Patients were classified into two groups based on irAEs of any grade: irAE positive and negative.
Results:
Of the 43 participants, 28 received ICI with chemotherapy and 15 received monotherapy. 18 of 43 patients (42%) were determined to have irAEs. These included the following: 9 pneumonitis, 3 thyroiditis, 3 adrenal insufficiency, 1 arthritis, 1 flare of pre-existing psoriasis, 1 mucositis, 1 colitis, 1 myocarditis, and 1 hepatitis (2 patients had both thyroiditis and adrenal insufficiency, 1 patient had both mucositis and pneumonitis). The median timeframe between treatment initiation and development of irAEs was 105 days [IQR, 42 - 169 days]. PSEA scores measured at 3 weeks after initiation of systemic therapy showed significant differences between irAE positive and negative groups in the following processes: extracellular matrix remodeling, complement activation, IFN-gamma signaling, and immune tolerance (P&lt;0.05 for PSEA scores of each pathway identified). These processes did not show any significant differences in PSEA scores at baseline. However, the changes in PSEA scores of all processes analyzed from baseline to 3 weeks after treatment initiation were not significantly different between the two groups.
Conclusions:
Our findings demonstrate that serum-based, proteomic scores can provide insight into understanding early mechanisms for the development of irAEs in patients treated with ICI. In particular, we identified several mechanisms associated with the development of irAEs, including extracellular matrix remodeling, complement activation, IFN-gamma signaling, and immune tolerance. These associations were not present at baseline and were only observed after treatment initiation, suggesting that early changes in the blood may provide insight into prediction of irAEs.
Citation Format: Andrew A. Davis, Jonghanne Park, Leeseul Kim, Gahyun Gim, Wade T. Iams, Michael S. Oh, Robert W. Lentz, Heinrich Roder, Joanna Roder, Senait Asmellash, Lelia Net, Julia Grigorieva, Nisha Mohindra, Victoria Villaflor, Young Kwang Chae. Serum proteomic scores for understanding the mechanisms of immune-related adverse events (irAEs) in non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5527.