Journal Article

Exploring the Potential Use of a PBMC-Based Functional Assay to Identify Predictive Biomarkers for Anti-PD-1 Immunotherapy

Fennell, Christie Jane, Akue, Adovi, KuKuruga, Mark A., Harper, Taylor A., Bacot, Silvia M., Lee, Shiowjen, Wang, Tao, Matthews, Rebecca L., Feldman, Gerald M.

2020

Overview

The absence of reliable, robust, and non-invasive biomarkers for anti- Programmed cell death protein 1 (PD-1) immunotherapy is an urgent unmet medical need for the treatment of cancer patients. No predictive biomarkers have been established based on the direct assessment of T cell functions, the primary mechanism of action of anti-PD-1 therapy. In this study, we established a model system to test T cell functions modulated by Nivolumab using anti-CD3 monoclonal antibody (mAb)-stimulated peripheral blood mononuclear cells (PBMCs), and characterized T cell functions primarily based on the knowledge gained from retrospective observations of patients treated with anti-PD-1 immunotherapy. During a comprehensive cytokine profile assessment to identify potential biomarkers, we found that Nivolumab increases expression of T helper type 1 (Th1) associated cytokines such as interferon-γ (IFN-γ) and interleukin-2 (IL-2) in a subset of donors. Furthermore, Nivolumab increases production of Th2, Th9, and Th17 associated cytokines, as well as many proinflammatory cytokines such as IL-6 in a subset of donors. Conversely, Nivolumab treatment has no impact on T cell proliferation, expression of CD25, CD69, or Granzyme B, and only modestly increases in the expansion of regulatory T cells. Our results suggest that assessment of cytokine production using a simple PBMC-based T cell functional assay could be used as a potential predictive marker for anti-PD-1 immunotherapy.

• Publisher: MDPI AG,MDPI
• Subject: Antigens, CD - metabolism / Biomarkers / Biomarkers - metabolism / Cancer / Cell Proliferation - drug effects / Cytokines / Cytokines - biosynthesis / Cytomegalovirus / Deoxyribonucleic acid / DNA / FDA approval / Flow cytometry / Granzymes - metabolism / Humans / Immunoassay / Immunotherapy / Leukocytes, Mononuclear - metabolism / Lymphocyte Activation - drug effects / Lymphocytes / Mutation / Nivolumab - pharmacology / Patients / Programmed Cell Death 1 Receptor - metabolism / T cell receptors / T-Lymphocytes, Regulatory - drug effects / T-Lymphocytes, Regulatory - immunology / Targeted cancer therapy / Th1 Cells - immunology / Tissue Donors