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An innovative multi-dimensional NGS approach to understanding the tumor microenvironment and evolution James H. Godsey, Ph.D. Vice President, Research & Development Clinical Sequencing Division (CSD) Life Science Solutions The world leader


  1. An innovative multi-dimensional NGS approach to understanding the tumor microenvironment and evolution James H. Godsey, Ph.D. Vice President, Research & Development Clinical Sequencing Division (CSD) Life Science Solutions The world leader in serving science For Research Use Only. Not for use in diagnostic procedures.

  2. CSD Vision and Strategy Leading the democratization of NGS to accelerate research and clinical applications Lead in oncology Targeted research Expand to applied Playing to win in With fast, simple, and scalable Bringing the power of NGS targeted applications sample to answer workflows to applied markets For Research Use Only. Not for use in diagnostic procedures. 2

  3. Growing Assay Menu Across All Key Applications Full characterization Routine research Translational Diagnostics of oncology samples Heme-oncology NSCLC Liquid biopsy Immuno-oncology Solid tumor + + + + solutions solutions solutions solutions solutions Oncomine ™ cfDNA Oncomine ™ Oncomine ™ Tumor Oncomine ™ Dx Target Oncomine ™ Myeloid Assays Comprehensive for Lung, Breast, Mutation Load Assay Test Research Assay Assay Colon Oncomine ™ Lung Oncomine ™ Immune Oncomine ™ Oncomine ™ Focus Childhood Cancer cfTNA Research Response Research Assay Research Assay Assay Assay Oncomine ™ Breast Oncomine ™ BRCA Oncomine TCR Beta- cfDNA Research Research Assay LR Assay Assay v2 Oncomine™ Pan - Oncomine TCR Beta- NEW Cancer Cell-Free SR Assay Assay Ion AmpliSeq HD NEW Custom cf Assays Ion AmpliSeq ™ Designer with Ion AmpliSeq ™ HD for custom panels For Research Use Only. Not for use in diagnostic procedures. 3

  4. Tumor-Immune Interactions are Complex and Warrant a Multi-Dimensional Approach Immune Repertoire Tumor Mutation Load Immune Response Source: http://www.sciencedirect.com/science/article/pii/S1074761313002963 For Research Use Only. Not for use in diagnostic procedures. 4 License: https://creativecommons.org/licenses/by/4.0/ Labels were removed.

  5. Growing Assay Menu Across All Key Applications Full characterization Routine research Translational Diagnostics of oncology samples Heme-oncology NSCLC Liquid biopsy Immuno-oncology Solid tumor + + + + solutions solutions solutions solutions solutions Oncomine ™ cfDNA Oncomine ™ Oncomine ™ Tumor Oncomine ™ Dx Target Oncomine ™ Myeloid Assays Comprehensive for Lung, Breast, Mutation Load Assay Test Research Assay Assay Colon Oncomine ™ Lung Oncomine ™ Immune Oncomine ™ Oncomine ™ Focus Childhood Cancer cfTNA Research Response Research Assay Research Assay Assay Assay Oncomine ™ Breast Oncomine ™ BRCA Oncomine TCR Beta- cfDNA Research Research Assay LR Assay Assay v2 Oncomine™ Pan - Oncomine TCR Beta- NEW Cancer Cell-Free SR Assay Assay Ion AmpliSeq HD NEW Custom cf Assays Ion AmpliSeq ™ Designer with Ion AmpliSeq ™ HD for custom panels For Research Use Only. Not for use in diagnostic procedures. 5

  6. Key Questions in Immuno-oncology Translational Research Biomarkers CAR-T Can characterizing the tumor Can we design superior therapeutic micro- environment (TME) predict T cells by influencing design and immune response? development through TCR sequencing? Can we improve a selection NGS Cancer Vaccines strategy for immune therapy clinical research trials? Can we design effective cancer Can we identify the population vaccines using the information predisposed to immune-mediated derived from TCR sequencing? adverse events? For Research Use Only. Not for use in diagnostic procedures. 6

  7. Interrogating the Tumor Microenvironment – A multi-dimensional approach Oncomine TCR Beta-SR Oncomine ™ Immune Oncomine Tumor Mutation Assay Response Research Assay Load Assay (Immune repertoire ( Targeted RNA-Seq) (Tumor mutation burden) TCR-Seq) • • • Quantifies somatic Profile 395 key genes Interrogates CDR3 of the associated with immune mutations from 1.7mb T-Cell Receptor beta response chain, for across 409 cancer genes characterization of for accurate assessment • Accurately measure immune status of tumor mutation burden gene expression over (TMB) • wide dynamic range Enables TCR monitoring • Correlates with response of minimal residual • to immune checkpoint Capture low expressing disease in the peripheral genes (IFNG) with blood inhibitors greater sensitivity For Research Use Only. Not for use in diagnostic procedures. 7

  8. Ion Torrent ™ Oncomine ™ TCR Beta – LR Assay | Makes the PBLs in Peripheral Blood an Additional Rich Source of Predictive Dx Information Sequencing Beta Long Read NGS assay capturing all 3 Chain of T Cell CDRs (1,2 &3). Uniquely captures germline TRBV polymorphism from Receptors to blood/tissue to investigate Characterize predisposition to adverse events. Immune Status Flexible input/sequencing depth 10ng- requirements covering samples with V-gene polymorphism Clonality / TCR convergence 1 m g low, medium, and high clonal diversity. Constant FR3 Leader FR1 FR2 CDR3 CDR1 CDR2 Variable (V) Diversity(D) Joining (J) Superior informatics for accurate clonality and β chain sequence AmpliSeq Primers ~325-400 bp assessment without interference from primer bias. Non-FFPE RNA Allelic variants alter interaction of CDR1 and 2 with HLA TCRComplex.png used under creative commons license: https://creativecommons.org/licenses/by-sa/3.0 For Research Use Only. Not for use in diagnostic procedures. 8

  9. TCR Convergence May Be a Hallmark of Chronic Antigen Stimulation Tumor Ag Priming and Tumor antigen continues Over time, convergent proliferation of tumor to prime naive T cells with TCR groups become antigen specific T cells. shared antigen specificity. detectable in peripheral T cells do not destroy blood. This distinguishes T cell tumor. responses to cancer from those following short-term acute antigen challenge typical of responses to infectious disease. For Research Use Only. Not for use in diagnostic procedures. 9

  10. TCR Profiling from Peripheral Blood May Provide the Most Direct Measurement of Tumor Immunogenicity Sequence of Events to Elicit Anti-Tumor T Cell Response • Convergent TCRs are the result of T cell responses Tumor acquires non- Tumor mutation burden to antigen, and thus may serve as a metric for synonymous mutation profiling (TMB) [indirect quantifying tumor immunogenicity. measure] • We propose that TCR convergence is a T cell Non-synonymous repertoire feature which preferentially arises mutation is translated following chronic antigen stimulation rather than the acute but transient antigen challenges elicited by Translated protein is infectious disease. broken into peptides • Given that tumor antigens may prime T cells over Peptide is presented HLA typing months or years time, measurements of TCR by HLA convergence may provide an accurate pre- treatment estimate of tumor immunogenicity. TCRβ sequencing of T cells recognize peripheral blood [direct peptide and proliferate measure] Anti-tumor T cell responses For Research Use Only. Not for use in diagnostic procedures. 10

  11. Improving Liquid Biopsy Through Sequencing of Peripheral Blood T Cells • Liquid biopsy is traditionally defined as the analysis of tumor cells, or the products of tumor cells, from peripheral blood. • cfDNA has been the standard input Oncomine ™ cfDNA Assays material for liquid biopsy. • However, signatures of T cell responses to tumor may be Oncomine ™ TCR Beta – LR Assay evaluated by T cell repertoire analysis of peripheral blood leukocytes. Image via Wikipedia For Research Use Only. Not for use in diagnostic procedures. 11

  12. Expanding Liquid Biopsy with Custom Panels Full characterization Routine research Translational Diagnostics of oncology samples Heme-oncology NSCLC Liquid biopsy Immuno-oncology Solid tumor + + + + solutions solutions solutions solutions solutions Oncomine ™ cfDNA Oncomine ™ Oncomine ™ Tumor Oncomine ™ Dx Target Oncomine ™ Myeloid Assays Comprehensive for Lung, Breast, Mutation Load Assay Test Research Assay Assay Colon Oncomine ™ Lung Oncomine ™ Immune Oncomine ™ Oncomine ™ Focus Childhood Cancer cfTNA Research Response Research Assay Research Assay Assay Assay Oncomine ™ Breast Oncomine ™ BRCA Oncomine TCR Beta- cfDNA Research Research Assay LR Assay Assay v2 Oncomine™ Pan - Oncomine TCR Beta- NEW Cancer Cell-Free SR Assay Assay Ion AmpliSeq HD NEW Custom cf Assays Ion AmpliSeq ™ Designer with Ion AmpliSeq ™ HD for custom panels For Research Use Only. Not for use in diagnostic procedures. 12

  13. Breakout Sensitivity, Standout Customization Introducing Ion AmpliSeq HD technology: New amplicon-based NGS library preparation technology that enables you to design custom ultra high-sensitivity panels for your targets of interest • Low limit of detection — variant detection down to 0.1%* enabled by unique molecular tags and dual barcodes • Customization in your hands — flexible panel design customization available at an accessible price • Complete 2-day workflow — fast targeted NGS workflow from sample to data *For cell-free DNA samples For Research Use Only. Not for use in diagnostic procedures. 13

  14. A Mission We Are Proud Of We enable our customers to make the world healthier, cleaner and safer. For Research Use Only. Not for use in diagnostic procedures. 14

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