1. Bristol-Myers Squibb is actively conducting translational medicine research to further our understanding of cancer biology and to identify which patient populations may be more likely to derive benefit from Immuno-Oncology (I-O) agents.

2. / Biomarkers and Pharmacodiagnostics (PDx) Imaging and Technologies
Bioinformatics and
Integrated Sciences
Clinical Pharmacology and
Pharmacometrics
Exploratory Translational Research
Collaboration 2

3. Biomarkers and Pharmacodiagnostics (PDx)
Imaging and Technologies /
Bioinformatics and
Integrated Sciences
Clinical Pharmacology and
Pharmacometrics
Exploratory Translational Research
Biomarkers and Pharmacodiagnostics (PDx)
Our vision is for tumor biology to inform treatment selection for each patient at each stage of therapy
Collaboration

4. Areas of Focus in Biomarker Research
Inflamed Tumor Microenvironment: Biomarkers within the tumor, T cells or microenvironment that may predict response
Tumor Antigens:
Biomarkers to identify hypermutation and neo-antigens that may predict response to I-O
Inflamed Tumor
Tumor
Antigen
Tumor Immune Suppression: Biomarkers related to mechanisms of resistance via specific immune pathways that may be addressed with I-O treatment
Host Environment:
Biomarkers to characterize the host environment, beyond the tumor microenvironment, which may reveal immune-related mechanisms predictive of response
Tumor Immune Suppression
Host Environment
Pharmacodiagnostics (PDx):
Diagnostic tests for biomarker expression that may predict patient response prior to treatment

5. Areas of Focus in Biomarker Research
Inflamed Tumor Microenvironment: Biomarkers within the tumor, T cells or microenvironment that may predict response
Tumor Antigens:
Biomarkers to identify hypermutation and neo-antigens that may predict response to I-O
For example, PD-L1 is expressed in a variety of healthy cell types and tumor cells. PD-L1 binds to the PD-1 receptor on T cells, inhibiting T cell activation.1-2 PD-L1 may be expressed only on a portion of the tumor cell and expression levels may change over time.3
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References:
Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):
Hobo W, Maas F, Adisty N, et al. siRNA silencing of PD- L1 and PD L2 on dendritic cells augments expansion and function of minor histocompatibility antigen–specific CD8+ T cells. Blood. 2010;116(22):
Kerr KM, Tsao MS, Nicholson AG, Yatabe Y, Wistuba II, Hirsch Fr. Programmed Death-Ligand 1 Immunohistochemistry in Lung Cancer In what state is this art?. J Thorac Oncol. 2015;10(7):  
Inflamed Tumor
Tumor
Antigen
Tumor Immune Suppression: Biomarkers related to mechanisms of resistance via specific immune pathways that may be addressed with I-O treatment
Host Environment:
Biomarkers to characterize the host environment, beyond the tumor microenvironment, which may reveal immune-related mechanisms predictive of response
Tumor Immune Suppression
Host Environment
Pharmacodiagnostics (PDx):
Diagnostic tests for biomarker expression that may predict patient response prior to treatment

6. Areas of Focus in Biomarker Research
Inflamed Tumor Microenvironment: Biomarkers within the tumor, T cells or microenvironment that may predict response
Tumor Antigens:
Biomarkers to identify hypermutation and neo-antigens that may predict response to I-O
References:
Stanley ER, Chitu V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol ;6:a
Zhu Y, Knolhoff BL, Meyer MA, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74(18):
Richardsen E, Uglehus RD, Johnsen SH, Busnd LT. Macrophage-colony stimulating factor (CSF1) predicts breast cancer progression and mortality. Anticancer Res. 2015;35(2):
Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):
Inflamed Tumor
Tumor
Antigen
Tumor Immune Suppression: Biomarkers related to mechanisms of resistance via specific immune pathways that may be addressed with I-O treatment
Host Environment:
Biomarkers to characterize the host environment, beyond the tumor microenvironment, which may reveal immune-related mechanisms predictive of response
Tumor Immune Suppression
Host Environment
For example, CSF1R is a receptor on the surface of macrophages and other cells of the myeloid lineage.1 High levels of CSF1, the ligand for CSF1R, may indicate that tumors are using CSF1R pathway to drive immunosuppression.2-4
Pharmacodiagnostics (PDx):
Diagnostic tests for biomarker expression that may predict patient response prior to treatment

7. Areas of Focus in Biomarker Research
Inflamed Tumor Microenvironment: Biomarkers within the tumor, T cells or microenvironment that may predict response
Tumor Antigens:
Biomarkers to identify hypermutation and neo-antigens that may predict response to I-O
For example, a growing body of research suggests that assessing the quantity of mutations carried by a tumor—the tumor mutation burden—may predict the likelihood that a patient could benefit from certain I-O therapies.1-3
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References:
Rizvi et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science ;348(6230):
Rosenberg et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):
Snyder et al. Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma. New England Journal of Medicine. 2014;371:
Inflamed Tumor
Tumor
Antigen
Tumor Immune Suppression: Biomarkers related to mechanisms of resistance via specific immune pathways that may be addressed with I-O treatment
Host Environment:
Biomarkers to characterize the host environment, beyond the tumor microenvironment, which may reveal immune-related mechanisms predictive of response
Tumor Immune Suppression
Host Environment
Pharmacodiagnostics (PDx):
Diagnostic tests for biomarker expression that may predict patient response prior to treatment

8. Areas of Focus in Biomarker Research
Inflamed Tumor Microenvironment: Biomarkers within the tumor, T cells or microenvironment that may predict response
Tumor Antigens:
Biomarkers to identify hypermutation and neo-antigens that may predict response to I-O
References:
Dietert, et al. Biomarkers for the 21st Century: Listening to the Microbiome. Toxicological Sciences. 144(2), 2015, 208–216
Inflamed Tumor
Tumor
Antigen
Tumor Immune Suppression: Biomarkers related to mechanisms of resistance via specific immune pathways that may be addressed with I-O treatment
Host Environment:
Biomarkers to characterize the host environment, beyond the tumor microenvironment, which may reveal immune-related mechanisms predictive of response
Tumor Immune Suppression
Host Environment
For example, markers in microorganisms (i.e., microbiome) may play a role in developing resistance to I-O treatment1
Pharmacodiagnostics (PDx):
Diagnostic tests for biomarker expression that may predict patient response prior to treatment

9. Tumor Immune Suppression Pharmacodiagnostics (PDx):
Inflamed Tumor Microenvironment: Biomarkers within the tumor, T cells or microenvironment that may predict response
Tumor Antigens:
Biomarkers to identify hypermutation and neo-antigens that may predict response to I-O
References:
FDA. PD-L1 IHC 28-8 pharmDx. P04163_01/SK / p c.pdf
Inflamed Tumor
Tumor
Antigen
Tumor Immune Suppression: Biomarkers related to mechanisms of resistance via specific immune pathways that may be addressed with I-O treatment
Host Environment:
Biomarkers to characterize the host environment, beyond the tumor microenvironment, which may reveal immune-related mechanisms predictive of response
Tumor Immune Suppression
Host Environment
PD-L1 assays are in vitro diagnostic tests used to detect PD-L1 in certain types of cancer. This test can help determine appropriate treatment. 1
Pharmacodiagnostics (PDx):
Diagnostic tests for biomarker expression that may predict patient response prior to treatment

10. Pharmacodiagnostics Inflamed Tumor Tumor Antigen
Biomarkers and Pharmacodiagnostics (PDx)
Imaging and Technologies /
Bioinformatics and
Integrated Sciences
Clinical Pharmacology and
Pharmacometrics
Exploratory Translational Research
Pharmacodiagnostics
Inflamed Tumor Microenvironment: Biomarkers within the tumor, T cells or microenvironment that may predict response
Tumor Antigens:
Biomarkers to identify hypermutation and neo-antigens that may predict response to I-O
References:
FDA. PD-L1 IHC 28-8 pharmDx. P04163_01/SK / p c.pdf
Inflamed Tumor
Tumor
Antigen
Tumor Immune Suppression: Biomarkers related to mechanisms of resistance via specific immune pathways that may be addressed with I-O treatment
Host Environment:
Biomarkers to characterize the host environment, beyond the tumor microenvironment, which may reveal immune-related mechanisms predictive of response
Tumor Immune Suppression
Host Environment
PD-L1 assays are in vitro diagnostic tests used to detect PD-L1 in certain types of cancer. This test can help determine appropriate treatment. 1
Collaboration
Pharmacodiagnostics (PDx)
Diagnostic tests for biomarker expression that may predict patient response prior to treatment

11. Imaging and Technologies
Biomarkers and Pharmacodiagnostics (PDx)
Imaging and Technologies /
Bioinformatics and
Integrated Sciences
Clinical Pharmacology and
Pharmacometrics
Exploratory Translational Research
Imaging and Technologies
State-of-the-art technology and complex analytical platforms help us answer basic research questions
Collaboration

12. FLOW CYTOMETRY & FUNCTIONAL BIOLOGY
IMAGING
Molecular imaging allows researchers to study specific targets and guide treatment decisions without invasive procedures
GENOMICS & GENETICS
Mapping, characterizing and quantifying gene expression and mutations to allow for a deeper understanding of disease biology and mechanisms of drug response
FLOW CYTOMETRY & FUNCTIONAL BIOLOGY
Method of single-cell analysis that allows for cell sorting, detection of disease biomarkers and a better understanding of cell biology
SAMPLE MANAGEMENT 
System for storing and organizing samples for efficient future use

13. / Biomarkers and Pharmacodiagnostics (PDx) Imaging and Technologies
Bioinformatics and
Integrated Sciences
Clinical Pharmacology and
Pharmacometrics
Exploratory Translational Research
IMAGING
Molecular imaging allows researchers to study specific targets and guide treatment decisions without invasive procedures
GENOMICS & GENETICS
Mapping, characterizing and quantifying gene expression and mutations to allow for a deeper understanding of disease biology and mechanisms of drug response
FLOW CYTOMETRY & FUNCTIONAL BIOLOGY
Method of single-cell analysis that allows for cell sorting, detection of disease biomarkers and a better understanding of cell biology
SAMPLE MANAGEMENT 
System for storing and organizing samples for efficient future use
Collaboration

14. Bioinformatics and Integrated Sciences
Biomarkers and Pharmacodiagnostics (PDx)
Imaging and Technologies /
Bioinformatics and
Integrated Sciences
Clinical Pharmacology and
Pharmacometrics
Exploratory Translational Research
Bioinformatics and Integrated Sciences
Applying cutting-edge methods for integrative analysis of large-scale, complex biological data and developing actionable insights to drive development
Collaboration

15. Gene expression network derived from analysis of TCGA RNA sequencing data
Loss of CDKN2A is associated with reduced estimates of T cells in the tumor microenvironment in some cancers
Our Translational Bioinformatics team uses cutting-edge methods to perform integrative data analysis. We study the interplay of tumor genomes, their regulation and the tumor microenvironment to further our understanding of response to I-O agents.
Our comprehensive analysis of The Cancer Genome Atlas (TCGA) identified networks of co-expressed genes that can be used to identify specific types of immune cells in the tumor microenvironment. In some tumors, certain genetic mutations correlate with the abundance of such cells.

16. Partnerships with leading data bioinformatics companies enhance our in-house capabilities.
Gene expression network derived from analysis of TCGA RNA sequencing data
Loss of CDKN2A is associated with reduced estimates of T cells in the tumor microenvironment in some cancers
Our Translational Bioinformatics team uses cutting-edge methods to perform integrative data analysis. We study the interplay of tumor genomes, their regulation and the tumor microenvironment to further our understanding of response to I-O agents.
Our comprehensive analysis of The Cancer Genome Atlas (TCGA) identified networks of co-expressed genes that can be used to identify specific types of immune cells in the tumor microenvironment. In some tumors, certain genetic mutations correlate with the abundance of such cells.
Our team analyzes tumor mutation burden, RNA sequencing, serum cytokine, and other large-scale biomarker data sets generated from clinical trials.

17. The mandate of integrated sciences is to integrate, analyze and synthesize data derived from both external and internal studies addressing fundamental translational questions in I-O to develop actionable insights and hypotheses that help drive discovery and clinical development

18. Biomarkers and Pharmacodiagnostics (PDx)
Imaging and Technologies /
Bioinformatics and
Integrated Sciences
Clinical Pharmacology and
Pharmacometrics
Exploratory Translational Research
The mandate of integrated sciences is to integrate, analyze and synthesize data derived from both external and internal studies addressing fundamental translational questions in I-O to develop actionable insights and hypotheses that help drive discovery and clinical development.
Collaboration

19. Clinical Pharmacology and Pharmacometrics (CP&P)
Biomarkers and Pharmacodiagnostics (PDx)
Imaging and Technologies /
Bioinformatics and
Integrated Sciences
Clinical Pharmacology and
Pharmacometrics
Exploratory Translational Research
Clinical Pharmacology and Pharmacometrics (CP&P)
Our combined CP&P team is fully integrated across all phases of development to validate MOA of novel targets using mechanistic modeling, predict how assets may work together in combination in humans and identify the optimal safe and effective dose in patients through modeling and simulation
Collaboration

20. Hypothesis Generation
Mechanistic Modeling (QSP) Fuels New Questions and Continued Exploration in Immuno-Oncology
Hypothesis Testing
Prior Knowledge
Hypothesis Testing
Model Application
Model Development
Hypothesis Generation

21. Hypothesis Generation
Mechanistic Modeling (QSP) Fuels New Questions and Continued Exploration in Immuno-Oncology
Hypothesis Testing
Prior Knowledge
Hypothesis Testing
The hypotheses simulated from the QSP model can be tested in clinical studies.
Prior knowledge can be integrated into a theoretical model of the cancer-immunity cycle.
Model Application
Model Development
Hypothesis Generation
The QSP model can then be used to generate hypotheses through simulation of potential clinical biomarker/tumor responses.
The theoretical model of the cancer-immunity cycle can be converted into a mathematical QSP model.

22. Biomarkers and Pharmacodiagnostics (PDx)
Imaging and Technologies /
Bioinformatics and
Integrated Sciences
Clinical Pharmacology and
Pharmacometrics
Exploratory Translational Research
Mechanistic Modeling (QSP) Fuels New Questions and Continued Exploration in Immuno-Oncology
Hypothesis Testing
Prior Knowledge
Hypothesis Testing
The hypotheses simulated from the QSP model can be tested in clinical studies.
Prior knowledge can be integrated into a theoretical model of the cancer-immunity cycle.
Model Application
Model Development
Hypothesis Generation
Collaboration
The QSP model can then be used to generate hypotheses through simulation of potential clinical biomarker/tumor responses.
The theoretical model of the cancer-immunity cycle can be converted into a mathematical QSP model.

23. Exploratory Translational Research
Biomarkers and Pharmacodiagnostics (PDx)
Imaging and Technologies /
Bioinformatics and
Integrated Sciences
Clinical Pharmacology and
Pharmacometrics
Exploratory Translational Research
Exploratory Translational Research
Experimentation generates internal data to enable scientific discovery
Collaboration

24. Experimentation provides the knowledge and data to form hypotheses that can be tested in the clinic
We leverage existing and advanced clinical assays to explore and test new hypotheses using biologic samples
Insights gained from this research can quickly be implemented in prospective clinical trials to enhance and accelerate our pipeline

25. Study of proteins and how they interact within tumor microenvironment.
Experimentation provides the knowledge and data to form hypotheses that can be tested in the clinic
We leverage existing and advanced clinical assays to explore and test new hypotheses using biologic samples
Insights gained from this research can quickly be implemented in prospective clinical trials to enhance and accelerate our pipeline
SINGLE CELL GENOMICS: Leveraging next generation technologies to examine sequence information from individual cells.
PROTEOMICS:
Study of proteins and how they interact within tumor microenvironment.

26. Conducting Research to Understand the Immune System in Patients with Cancer
TISSUE
BLOOD
Genetics/genomics experiments to tissue samples
Fresh tissue
Whole Blood
Comprehensive phenotyping
Cell isolation for functional assays
Functional assays:
signaling, cytokine induction
PBMC
FFPE
Plasma
Plasma analytes
IHC/Proteomics
Mass Spectrometry
Gene expression:
mRNA and miRNA
Frozen tissue
PAXgene

27. Biomarkers and Pharmacodiagnostics (PDx)
Imaging and Technologies /
Bioinformatics and
Integrated Sciences
Clinical Pharmacology and
Pharmacometrics
Exploratory Translational Research
Conducting Research to Understand the Immune System in Patients with Cancer
TISSUE
BLOOD
Genetics/genomics experiments to tissue samples
Fresh tissue
Whole Blood
Comprehensive phenotyping
Cell isolation for functional assays
Functional assays:
signaling, cytokine induction
PBMC
FFPE
Plasma
Plasma analytes
IHC/Proteomics
Mass Spectrometry
Collaboration
Gene expression:
mRNA and miRNA
Frozen tissue
PAXgene

28. Biomarkers and Pharmacodiagnostics (PDx)
Imaging and Technologies /
Bioinformatics and
Integrated Sciences
Clinical Pharmacology and
Pharmacometrics
Exploratory Translational Research
Collaboration
Bristol-Myers Squibb has long believed the future of cancer research is dependent on investments in science and partnerships. Collaboration is integrated into our organizational framework across translational medicine and R&D
Collaboration

29. ACADEMIC COLLABORATION
Our scientific collaborations with academic centers around the globe expand our research capabilities and accelerate our collective ability to advance the science.
ACADEMIC COLLABORATION
We seek to partner with other I-O experts to expand our translational medicine capabilities.
BUSINESS DEVELOPMENT

30. ACADEMIC COLLABORATION
A global peer-to-peer collaboration between Bristol-Myers Squibb and academia that aims to advance I-O science and translational medicine to benefit patients.
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Our scientific collaborations with academic centers around the globe expand our research capabilities and accelerate our collective ability to advance the science.
ACADEMIC COLLABORATION
Research collaborations with select European research institutions to appropriately accelerate, expand and more effectively advance I-O research.
We seek to partner with other I-O experts to expand our translational medicine capabilities.
Working with partners like Foundation Medicine and GRAIL helps to drive the identification, validation and application of predictive biomarkers.
BUSINESS DEVELOPMENT

31. Our robust translational medicine program informs key areas of research, including:
Disease targeting and responsive patient segmentation
Ideal treatment strategies, including combinations, for each patient
Optimal dosing, schedule and clear understanding of MOA