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BMS Translational Medicine 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. Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics Research / Collaboration Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics Research / Biomarkers and Pharmacodiagnostics (PDx) Our vision is for tumor biology to inform treatment selection for each patient at each stage of therapy Collaboration Areas of Focus in Biomarker Research Inflamed Tumor Tumor Antigens: Microenvironment: Biomarkers to identify Biomarkers within the tumor, T hypermutation and neo- cells or microenvironment that antigens that may predict may predict response response to I-O Inflamed Tumor Tumor Antigen Tumor Immune Host Environment: Suppression: Biomarkers to characterize the Biomarkers related to host environment, beyond the mechanisms of resistance via Tumor Immune tumor microenvironment, which specific immune pathways that Suppression may reveal immune-related may be addressed with I-O mechanisms predictive of treatment response Pharmacodiagnostics (PDx): Diagnostic tests for biomarker expression that may predict patient response prior to treatment Areas of Focus in Biomarker Research Inflamed Tumor Microenvironment: For example, PD-L1 is expressed in a Biomarkers within the tumor, T variety of healthy cell types and tumor cells. PD-L1 binds to the PD-1 receptor cells or microenvironment that on T cells, inhibiting T cell activation.1-2 may predict response PD-L1 may be expressed only on a portion of the tumor cell and expression levels may change overInflamed time.3 Tumor CLICK TO VIEW VIDEO > Tumor Antigen Tumor Immune Suppression Areas of Focus in Biomarker Research Inflamed Tumor Tumor Antigen Tumor Immune Suppression: Biomarkers related to mechanisms of resistance via Tumor Immune specific immune pathways that Suppression may be addressed with I-O treatment 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 Areas of Focus in Biomarker Research Tumor Antigens: Biomarkers to identify For example, a growing body hypermutationof and neo- research suggests that assessing the quantity of mutations carriedantigens by that may predict a tumor—the tumor mutation response to I-O burden—may predict the likelihood that a patient could benefit from Inflamed Tumor certain I-O therapies.1-3 Tumor Antigen CLICK TO LEARN MORE > Tumor Immune Suppression Areas of Focus in Biomarker Research Inflamed Tumor Tumor Antigen Host Environment: Biomarkers to characterize the host environment, beyond the Tumor Immune tumor microenvironment, which Suppression may reveal immune-related mechanisms predictive of response For example, markers in microorganisms (i.e., microbiome) may play a role in developing resistance to I-O treatment1 Pharmacodiagnostics Inflamed Tumor Tumor Antigen Tumor Immune Suppression 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 Pharmacodiagnostics Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics Research Inflamed Tumor Tumor Antigen / Tumor Immune Suppression 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 Collaborationthat may predict patient response prior to treatment Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics Research Imaging and Technologies State-of-the-art technology / and complex analytical platforms help us answer basic research questions Collaboration IMAGING GENOMICS & FLOW CYTOMETRY & SAMPLE GENETICS FUNCTIONAL BIOLOGY MANAGEMENT Molecular imaging allows Mapping, characterizing and Method of single-cell System for storing and researchers to study specific quantifying gene expression analysis that allows for cell organizing samples for targets and guide treatment and mutations to allow for a sorting, detection of disease efficient future use decisions without invasive deeper understanding of biomarkers and a better procedures disease biology and understanding of cell mechanisms of drug biology response Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics Research IMAGING GENOMICS & FLOW CYTOMETRY & SAMPLE GENETICS / FUNCTIONAL BIOLOGY MANAGEMENT Molecular imaging allows Mapping, characterizing and Method of single-cell System for storing and researchers to study specific quantifying gene expression analysis that allows for cell organizing samples for targets and guide treatment and mutations to allow for a sorting, detection of disease efficient future use decisions without invasive deeper understanding of biomarkers and a better procedures disease biology and understanding of cell mechanisms of drug biology response Collaboration Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics 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 Gene expression network derived from analysis of Loss of CDKN2A is associated with TCGA RNA sequencing data 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. Partnerships with leading data bioinformatics companies enhance our in-house capabilities. Gene expression network derived from analysis of Loss of CDKN2A is associated with TCGA RNA sequencing data 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 Our team analyzes tumor mutation agents. burden, RNA sequencing, serum cytokine, and other large-scale biomarker data sets generated from Our comprehensive analysis of The Cancer Genome Atlas (TCGA) identified clinical trials. 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. 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 Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics 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 Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics 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 Mechanistic Modeling (QSP) Fuels New Questions and Continued Exploration in Immuno-Oncology Hypothesis Testing Prior Knowledge Hypothesis Testing Model Application Model Development Hypothesis dx 1 = f ()x , x ,..., x Generation dt 1 1 2 n dx 2 = f ()x , x ,..., x dt 2 1 2 n ... dx n = f ()x , x ,..., x dt n 1 2 n Mechanistic Modeling (QSP) Fuels New Questions and Continued Exploration in Immuno-Oncology Hypothesis Testing Prior Knowledge
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