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Monitoring PD-1-Blocking Antibodies Bound to T Cells Derived from a Drop of Peripheral Blood
Published on: February 5, 2020
Exploring the Potential Use of a PBMC-Based Functional Assay to Identify Predictive Biomarkers for Anti-PD-1
Silvia M Bacot1, Taylor A Harper1, Rebecca L Matthews1
1Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Abstract:
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.
Insights
Predicting anti-Programmed cell death protein 1 (PD-1) immunotherapy response is crucial. This study suggests that assessing T cell cytokine production in peripheral blood mononuclear cells (PBMCs) could serve as a novel predictive biomarker for immunotherapy effectiveness.
Area of Science:
- Immunology
- Oncology
- Biomarker Discovery
Background:
- Reliable biomarkers for anti-Programmed cell death protein 1 (PD-1) immunotherapy are lacking, representing a significant unmet need in cancer treatment.
- Current predictive markers do not directly assess T cell functions, the core mechanism of anti-PD-1 therapy.
Purpose of the Study:
- To establish a model system for testing T cell functions modulated by Nivolumab.
- To identify potential predictive biomarkers for anti-PD-1 immunotherapy response based on T cell functional assays.
Main Methods:
- Utilized anti-CD3 monoclonal antibody (mAb)-stimulated peripheral blood mononuclear cells (PBMCs) to model T cell responses to Nivolumab.
- Conducted comprehensive cytokine profiling to assess changes in T cell function.
- Evaluated T cell proliferation, surface marker expression (CD25, CD69), Granzyme B, and regulatory T cell expansion.
Main Results:
- Nivolumab increased the expression of T helper type 1 (Th1) cytokines, including interferon-γ (IFN-γ) and interleukin-2 (IL-2), in a subset of donors.
- Nivolumab also enhanced the production of Th2, Th9, Th17, and pro-inflammatory cytokines like IL-6 in some individuals.
- No significant impact was observed on T cell proliferation, CD25/CD69 expression, or Granzyme B, with only a modest increase in regulatory T cells.
Conclusions:
- Assessment of cytokine production via a simple PBMC-based T cell functional assay shows promise as a predictive marker for anti-PD-1 immunotherapy.
- This approach could address the unmet need for reliable, non-invasive biomarkers in cancer immunotherapy.
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