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

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 pri...

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Veröffentlicht in:	International journal of molecular sciences Jg. 21; H. 23; S. 9023
Hauptverfasser:	Bacot, Silvia M., Harper, Taylor A., Matthews, Rebecca L., Fennell, Christie Jane, Akue, Adovi, KuKuruga, Mark A., Lee, Shiowjen, Wang, Tao, Feldman, Gerald M.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	Switzerland MDPI AG 27.11.2020 MDPI
Schlagworte:	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 peripheral blood mononuclear cells cytokines T cells biomarker Nivolumab
ISSN:	1422-0067, 1661-6596, 1422-0067
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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.
AbstractList	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. 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.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.
Author	Fennell, Christie Jane Akue, Adovi KuKuruga, Mark A. Harper, Taylor A. Bacot, Silvia M. Lee, Shiowjen Wang, Tao Matthews, Rebecca L. Feldman, Gerald M.
AuthorAffiliation	3 Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; Shiowjen.Lee@fda.hhs.gov 1 Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; Silvia.Bacot@fda.hhs.gov (S.M.B.); tah9h@virginia.edu (T.A.H.); rebecca.matthews@nih.gov (R.L.M.); ChristieJane.Fennell@fda.hhs.gov (C.J.F.) 2 Office of Vaccines Research & Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; Adovi.Akue@fda.hhs.gov (A.A.); Mark.Kukuruga@fda.hhs.gov (M.A.K.)
AuthorAffiliation_xml	– name: 3 Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; Shiowjen.Lee@fda.hhs.gov – name: 1 Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; Silvia.Bacot@fda.hhs.gov (S.M.B.); tah9h@virginia.edu (T.A.H.); rebecca.matthews@nih.gov (R.L.M.); ChristieJane.Fennell@fda.hhs.gov (C.J.F.) – name: 2 Office of Vaccines Research & Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; Adovi.Akue@fda.hhs.gov (A.A.); Mark.Kukuruga@fda.hhs.gov (M.A.K.)
Author_xml	– sequence: 1 givenname: Silvia M. surname: Bacot fullname: Bacot, Silvia M. – sequence: 2 givenname: Taylor A. orcidid: 0000-0002-6088-1028 surname: Harper fullname: Harper, Taylor A. – sequence: 3 givenname: Rebecca L. orcidid: 0000-0001-7420-9374 surname: Matthews fullname: Matthews, Rebecca L. – sequence: 4 givenname: Christie Jane surname: Fennell fullname: Fennell, Christie Jane – sequence: 5 givenname: Adovi surname: Akue fullname: Akue, Adovi – sequence: 6 givenname: Mark A. surname: KuKuruga fullname: KuKuruga, Mark A. – sequence: 7 givenname: Shiowjen surname: Lee fullname: Lee, Shiowjen – sequence: 8 givenname: Tao orcidid: 0000-0002-1153-3430 surname: Wang fullname: Wang, Tao – sequence: 9 givenname: Gerald M. surname: Feldman fullname: Feldman, Gerald M.
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Keywords	peripheral blood mononuclear cells cytokines T cells biomarker Nivolumab
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Current address: Cancer ImmunoPrevention Laboratory, Vaccine, Immunity, and Cancer Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. Current address: Flow Cytometry Core Facility, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA. These authors contributed equally to this paper.
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Snippet	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...
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SubjectTerms	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
Title	Exploring the Potential Use of a PBMC-Based Functional Assay to Identify Predictive Biomarkers for Anti-PD-1 Immunotherapy
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