On Enabling High­-Quality Companion Diagnostic Applications via DNA Sequencing

Bahram G. Kermani, Founder, CEO

Crystal Genetics

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On Enabling High­-Quality Companion Diagnostic Applications via DNA Sequencing

Next­Generation Sequencing (NGS) has been successfully applied in different applications, many of which have high demand on the quality. Companion Diagnostics (cDx) is one such application, where adverse drug reactions (ADR) including toxicity could have detrimental effects on patients receiving such drugs. We propose a novel suite of genome analysis tools by which high­quality NGS­based cDx solutions can be enabled. Moreover, the efficiency of these tools in discovery of both single nucleotide variants (SNVs) and insertions/deletions (InDels) could facilitate the discovery of biomarkers in cDx­related clinical trials. We applied whole genome sequencing (WGS) and whole exome sequencing (WES) data to a panel of genes that were suggested to contain potential variations for drug efficiency, toxicity, and/or dose response. The gene panel comprised those with germline or somatic marker(s) associated with chemotherapy response (GSTP1), hematological/hematopoietic toxicity (MTHFR), hepatic toxicity (ABCB1, SLC19A1), Warfarin dose response (VKORC1, CYP2A6), Deoxygalactonojirimycin response (GLA), Ivacaftor efficiency (CFTR), CDA’s adverse effects (G6PD), Statin response (APOE), and Gefitinib response (EGFR). To showcase feasibility, we used a subset data from breast cancer patients in the International Cancer Genome Consortium (ICGC). The raw data from these samples were run using Crystal Genetics’ proprietary genome analysis pipeline. By leveraging the power of novel genome assembly, signal processing, expert systems and deep learning, this pipeline is able to make accurate calls. To gauge the quality of the results, our proprietary in­silico verification (ISV) tool was employed. By presenting a rich multi­dimensional graphical/textual information to the expert user, ISV provides the “safety net” that the calls do indeed have the sufficient evidence, and therefore can be trusted. The “safety net” property is of paramount importance in cDx applications in order to guarantee a high quality biomarker detection from NGS data, especially when the underlying markers can have detrimental effects on the patient. In summary, we propose a methodology comprising the tandem use of novel genome analysis and in­silico verification tools, for high­quality discovery/identification of cDx biomarkers, used in in the field and in clinical trials.

Flow Cytometry as Routine Assay in the Clinic and as CDx: What does it take?

Anka Ehrhardt, Consultant

Former BMS

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Flow Cytometry as Routine Assay in the Clinic and as CDx: What does it take?

With its power to characterize the status of the immune system, flow cytometry is a key technology in evaluating the immune status of a patient, and changes in response to treatment, important information, e.g. in immunooncology, and a candidate for CDx. Flow cytometry is traditionally a method between science and art, suited for discovery work, useful in pre-clinical work, and difficult in clinical studies. With fast new developments in the technologies used in flow cytometry, the road is open to shape flow cytometry to overcome the typical challenges in the clinic (most notably, sample stability and assay reproducibility). This presentation will outline a strategy using the power of simple tools (such as selecting the right blood collection tube, standardization and normalization) and disruptive new technologies for point-of-care walk-away sample analysis in bringing flow cytometry assays up to the level of robustness required under real-life conditions

A unified big data based approach for matching treatment with individuals innate dynamics.

Yoav Smith, Manager Genomic Data Analysis Unit

Genefron, Hebrew University of Jerusalem, Medicine Faculty

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A unified big data based approach for matching treatment with individuals innate dynamics.

We studied a large number of expression arrays where the innate system was triggered either by viruses (HCV ,CMV..) or by autoimmune diseases (MS,RA..). We were able to fit a mathematical model accurately showing the dynamic response of individuals based on a small number of selected genes. Diagnostic kits were build based on these genomic signatures and verified for predicting patient response parallel to their treatment in hospital clinical departments.

Immune Checkpoint Inhibitor LAG3 Diagnostic Biomarker for Risk Stratification in Cardiovascular Disease and Oncology

Annabelle Rodriguez, Founder

Lipid Genomics

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Immune Checkpoint Inhibitor LAG3 Diagnostic Biomarker for Risk Stratification in Cardiovascular Disease and Oncology

The mission at Lipid Genomics is to prevent harm to patients who unknowingly suffer from deficiency of the immune checkpoint inhibitor, lymphocyte activation gene-3 (LAG3), and are at a high risk for serious adverse events due to current immune checkpoint inhibitor treatment. Immune checkpoint inhibitors are now commonly used in the clinical treatment of various malignancies. There now have emerged serious adverse events related to the use of these inhibitors, especially with dual inhibition, that include autoimmune and cardiovascular diseases. Using precision medicine approaches, we first identified that carriers of the risk allele for the rs10846744 single nucleotide polymorphism in the HDL cholesterol receptor, scavenger receptor class B type I (SCARB1) gene had significantly increased risk for cardiovascular disease (CVD) (odds ratio 1.50) in participants of the Multi-Ethic Study of Atherosclerosis (MESA). We then used in vitro approaches to show a novel connection between SCARB1 rs10846744 and the LAG3 gene, both located on human chromosome 12. Using in vitro approaches, we found that LAG3 protein deficiency was significantly associated with increased secretion of pro-inflammatory cytokines such as TNFα and lower secretion of anti-inflammatory IL-10, disturbances in cell signaling function, and impairment of HDL-mediated cholesterol efflux capacity. In MESA participants we observed an increased risk for CVD in subjects with LAG3 protein deficiency and high HDL-C levels (odds ratio 1.45). Lipid Genomics has exclusive licensing rights for a LAG3 diagnostic test [patent pending]. The LAG3 assay is an ELISA and there is no commercially available LAG3 assay for clinical use. Lipid Genomics has exclusive licensing rights for a soluble LAG3 biologic [patent pending] as a potential replacement and/or rescue treatment. The LAG3 biologic is currently in pre-clinical studies. Lipid Genomics is uniquely positioned to advance development of the LAG3 diagnostic for clinical utility in autoimmune, cardiovascular, and oncology diseases. Moreover, Lipid Genomics will be advancing the LAG3 biologic to suppress inflammation in subjects identified as LAG3 deficiency based on the use of the LAG3 diagnostic test.