Abstract 5526: Serum proteomic scores for understanding response and mechanisms of resistance to immune checkpoint inhibitors in non-small cell lung cancer
Authors: Andrew A. Davis, Jonghanne Park, 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
Journal: Cancer Research (2020)

Abstract Background: Understanding of biological processes associated with response and resistance to immune checkpoint inhibitors (ICI) with or without chemotherapy is limited. We used serum-based, proteomic scores at baseline and after treatment initiation to explore mechanisms of early resistance 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 (Th1), complement, interferon (IFN)-gamma). Statistical associations with clinical response data using RECIST, progression-free survival (PFS), and overall survival (OS) were examined. The distribution of each PSEA score at baseline and 3 weeks was compared for patients with progression of disease (PD) as best response or PFS &amp;lt;6 months classified as “Early PD" vs. patients with best response of SD, PR or CR and PFS ≥6 months as “no Early PD” using mixed effect models, with no adjustments for multiple comparisons. Results: Of the 43 participants, 28 received ICI with chemotherapy and 15 received as monotherapy. 31 of 43 patients (72%) were treatment naïve at baseline blood collection. PSEA scores measured at 3 weeks after initiation of systemic therapy showed significant differences between the Early PD (N=25) and no Early PD (N=18) groups in complement activation, IFN-gamma, Th1, and immune tolerance. In contrast, no differences in PSEA scores were observed in baseline measurements. For three biological processes (complement, IFN-gamma, immune tolerance), the differences in PSEA scores between the Early and no Early PD groups were more prominent with measurements at 3 weeks (Pinteraction &amp;lt; 0.05). Conclusions: Collectively, these data demonstrate the potential utility of serum-based, proteomic scores to provide insight into mechanisms for early disease progression for patients treated with ICI. We identified several resistance mechanisms including complement activation, IFN-gamma signaling, and immune tolerance. The observed associations were more prominent after one cycle of treatment, suggesting that for a subset of patients early changes in the blood after treatment initiation may provide insight into mechanisms of resistance to ICI. Citation Format: Andrew A. Davis, Jonghanne Park, 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 response and mechanisms of resistance to immune checkpoint inhibitors 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 5526.