Biomarkers in Alzheimer’s Disease and Immuno-Oncology
Vice President and Head of Translational Biomarkers
Merck Research Laboratories
Biomarkers are critical to the development and use of precision medicines. This talk will consider the use of molecular and imaging biomarkers in Alzheimer’s disease and immuno-oncology. Use of biomarkers for early diagnosis of Alzheimer’s Disease and following its pathophysiological changes has recently been widely recognized as critical to development of drugs to alter disease progression. Multiple biomarkers have potential to help identify patients most likely to benefit from checkpoint inhibitors, including PD-L1 IHC, MSI-H/dMMR and potentially TMB.
Factors that Impact the Delivery of Precision Medicine: The Role of Biomarkers, Companion Diagnostics and Advanced Therapies
Steve Anderson, PhD
Chief Scientific Office,
Senior Vice President
Recent examples of successful cell and gene therapies in Oncology and Rare Diseases provide proof points for the rapidly evolving precision medicine landscape. Biomarkers relevant to disease biology and therapeutic approaches to managing disease are now found in over 300 drug labels. In 2018, over 40% of the approved therapies had a precision medicine approach for their drug development strategy. In addition, approximately 40 companion diagnostic assays are currently used in clinical practice, with the vast majority applied in Oncology. Each of these examples supports the increased focus in both drug development and in diagnostics on the importance of precision medicine in diagnosing and managing disease. In addition to the better understanding of disease biology other factors are also helping to improve on such applications, including rapidly evolving laboratory technologies and the associated bioinformatics and data analytical tools. Lastly various commercial factors are becoming increasingly important for the broad delivery of precision medicine. Each of these areas along with other relevant topics that help drive the development and adoption of precision medicine approaches will be reviewed.
Data Driven Treatment Strategies
Matthew Clark, Ph. D.
Director, Scientific Services
Elsevier has partnered with heathcare organizations to study the use of data to optimize treatments for patients with rare diseases. These partnerships combine pathway, mutation, efficacy and adverse event information mined from scientific publications with medical expertise and real-world experience of physicians specializing in treating these diseases. Elsevier is in a unique position as a publisher of medical information for nearly 150 years to mine detailed facts from reports of treatments, including efficacy, biology, and relevant mutations. This vast data is being analyzed with machine learning to understand how to select optimal treatments based on personalized disease biology of the patient, as well as to identify approved drugs that can be repurposed to treat otherwise intractable conditions
Companion Diagnostic Development in Gene Expression for Challenging Sample Types
Vice President, Scientific Collaborations
HTG Molecular, PLATINUM SPONSOR
There is a current need to perform molecular testing on a variety of sample types in the clinical lab; FFPE, frozen tissue, plasma, serum, and cell lysates. Large collections – both current and archival – are available, often with links to patient outcomes making them ideal for companion diagnostic development. A limitation to the utilization of this resource is the difficulty of nucleic acid extraction from small or degraded samples. In the case of FFPE, crosslinking-induced fragmentation of nucleic acids makes extraction and downstream analysis time-consuming and difficult, especially when scaling up into routine clinical profiling. In the case of plasma/serum, large amounts of this sample type are usually required to produce enough isolated RNA to test by traditional methods. HTG has developed EdgeSeq, a coupling of RNA extraction-free nuclease protection assay (qNPA) with next generation sequencing (NGS) – mediated quantification.
Genome-wide cell-free DNA fragmentation in patients with cancer
Nicholas Dracopoli, Ph.D.
Chief Scientific Officer,
Liquid biopsies used to screen for early cancers or to monitor treatment response in cancer patients have relied on finding somatic alterations (including mutations, translocations and copy number variation) in the cancer cells. Detecting these somatic variants in blood samples requires deep sequencing to find the rare mutant DNA fragments in the complex mix of lymphocyte and tumor DNA circulating in the blood. We propose an alternative method for the early detection of cancer that does not rely on identifying rare mutant DNA fragments, but on detecting the ubiquitous consequences of these mutations in cancer cells. We have developed a sequencing method (Cristiano et al., 2019) that identifies abnormal DNA packaging in cancer cells that can be used to distinguish DNA derived from epithelial cancer cells from normal lymphocyte DNA in the blood. This method uses machine-learning analyses of DNA fragmentation patterns from low coverage whole genome sequencing (WGS) libraries of plasma DNA. This method has demonstrated high sensitivity and specificity for the detection of pre-metastatic (Stage I-III) and metastatic cancer (Stage IV) in seven different cancers. Further analyses of these altered DNA fragmentation patterns in plasma DNA may lead to the eventual development of a highly sensitive and specific screening test for cancer.
Beyond BRCA: Homologous Recombination Repair
Executive Director, Companion Diagnostics and Genomics,
Merck & Co.
The therapeutic benefit of PARP inhibition in BRCA-mutated ovarian and breast cancer is well established. Emerging data suggest this therapeutic benefit may extend to other indications and to patients harboring other defects in the homologous recombination repair pathway. Multiple predictive biomarkers are being studied in clinical trials. Yet applying precision medicine in this case, however, is far from simple since there are different biomarker tests with different definitions of biomarkers, different PARP inhibitors and differential effects of rare mutations in different tumor types. We will describe potential predictive biomarker assays for response to PARP inhibition, as well as the potential routes and challenges to their development into companion diagnostic tests.
Translational research in hematological cancers
Team Lead, Oncology
Approximately every 9 minutes someone in the US dies from a blood cancer. Modulation of the immune system to reject cancer cells has revolutionized the treatment landscape in cancer. In hematological malignancies, the introduction of immunomodulatory drugs and antibody therapies has significantly increased survival. Despite high rates of early response, many people relapse after treatment, and new agents are needed. I will present how translational medicine integrates with other pharma functions to support clinical development in hematological cancers, introducing examples that illustrate how biomarkers have impacted successful drug development.
Evolution of the Liquid Biopsy in Metastatic Prostate Cancer
Professor of Urology
Thomas Jefferson University
I will review the biologic, prognostic, and predictive significance of circulating prostate cancer tumor cells (CTCs), and circulating tumor DNA (ctDNA) in the blood of metastatic castration resistant prostate cancer patients (mCRPC). CTCs demonstrate robust prognostic value independent of PSA in predicting overall survival. The CTC androgen receptor variant receptor 7 (AR-V7) phenotype predicts resistance to androgen receptor synthesis inhibitors and sensitivity to taxane based chemotherapy in mCRPC patients who are candidates for second line therapy. Research is rapidly pivoting toward ctDNA analysis because the approach is sensitive, prognostic, cost-effective, and it can elucidate mechanisms of systemic therapy. I will outline our approach to translating liquid biopsy research in our large urology group private practice.
First Principles Innovation – Perspectives on Pain Points and Unmet Needs in Precision Oncology.
Advances in precision medicine have resulted in significant improvements in cancer care, however, challenges and pain points persist across the entire precision medicine spectrum, creating opportunities for value creation through the development of tools, technologies, and solutions that alleviate these pain points. Too often, however, innovative technologies, products, and services are developed without a clear understanding of the unmet needs or pain points these tools are best suited to address (if any), or whether the perceived value propositions resonate with their customers and users. To elucidate the primary areas of unmet need and the most significant pain points in precision medicine today, we have conducted interviews with a variety of stakeholders across the precision medicine spectrum to pinpoint and characterize pain points and unmet needs from an unbiased perspective. We discuss how key pain points differ by stakeholder type and identify areas and applications towards which innovation and development efforts can be directed.
Expert Perspectives on Disruption and Evolution in Precision Oncology.
The capabilities of the tools, technologies, and methods for studying, diagnosing, and treating cancer are advancing more rapidly than ever. With the convergence of comprehensive and precise molecular profiling (e.g., single-cell and spatial-omics, digital molecular quantification, ultra-high multiplexing and multo-omics), healthcare digitalization and consumerization (e.g., EHR, real-world outcomes and activity data), and advanced analytics (e.g., artificial intelligence, machine learning, image analysis), the information gathered and analyzed today will lay the foundation for a future of precision medicine that may look profoundly different. To ascertain how the precision medicine landscape might evolve in the long term, we interviewed various KOLs to gather diverse perspectives on the evolution of cancer care and potentially-disruptive scenarios to the current precision medicine paradigm. We discuss these scenarios, as well as their drivers and moderators, and the potential implications for current precision medicine stakeholders.
RNASeq as the Technology Choice in Biomarker Discovery
Biomarker Research Manager
Regulatory landscape for AI Powered algorithms in digital pathology
VP Regulatory Affairs, Clinical Affairs and Strategic Business Development
AI systems should improve patient management and support health care providers. Building effective AI systems will require the increased utilization of digital technologies to enable the digitization and aggregation of large sets of harmonized data for machine learning. While digitization is already routine in many areas of medicine (e.g., radiology, electronic health records), digitization of pathology slides is still uncommon. Major challenges to the adoption of digitization in pathology include technological, financial and regulatory factors. Oversight and regulation of healthcare AI systems are required and remain based on benefit risk ratio, which accounts for factors such as intended use; evidence of safety and efficacy. Unique challenges that AI systems present include use of post-market (real world) data to control quality, monitor performance, and continuously learn. Successful deployment of AI systems in the real world will require interoperability between devices and additional clarity around responsibilities between the developers and end-users. To begin to address these issues, the FDA has developed several initiatives, such as the Digital Health Initiative and the position paper on AI. During this presentation, we will discuss the regulatory landscape with a focus on pathology and the US market.
Enabling Companion Diagnostic Development for Challenging Biomarkers with RNAscope
Chief Medical Officer
While immunohistochemistry and DNA FISH have gained widespread adoption in both clinical and companion diagnostic applications over the last twenty years, RNA ISH has lagged behind these methods due to its poor sensitivity and absence of automation. Recent advances in RNA ISH technology have made the technique more sensitive as well as specific and allowed for the development of automated protocols on commercially available staining platforms. The RNAscope RNA ISH technology can now detect RNA expression down to the single mRNA copy level in quantitative, automated, chromogenic assays in FFPE tissues, allowing for biomarker assessment in the cellular and morphologic context by diagnosticians at the light microscope. As a result of these advances, RNA ISH has become a valuable tool for determining the expression status of biomarkers across the spectrum of human diseases in a variety of diagnostic applications as well as an attractive platform for companion diagnostics. This presentation will review how the RNAscope RNA ISH technology addresses various issues with IHC and other CDx platforms and how it is being used in CDx development for a variety of challenging biomarkers
Use of AI-Powered Pathology to enable New Insights into the Biology underlying Tumor Resistance to IO Therapies
The field of immuno-oncology (IO) has advanced tremendously over the past decade. However, resistance to IO therapies remains a major clinical challenge. In this talk, we will discuss the use of AI-powered pathology to enable new insights into the biology underlying tumor resistance to IO therapies and describe the potential for AI-powered CDx to enable more effective patient selection for IO treatments in clinical research and practice.
From a streamlined Companion Diagnostic to a Next Generation Sequencing Analysis in Acute Myeloid Leukemia: opportunities and challenges
Director of Companion Diagnostics
Internal tandem duplications in fms-like tyrosine kinase 3 (FLT3-ITD) are common in Acute Myeloid Leukemia (AML) and confer a poor prognosis. The LeukoStrat® CDx FLT3 Mutation Assay is a PCR-based in vitro diagnostic test designed to detect FLT3 internal tandem duplications (ITD) mutations and tyrosine kinase domain (TKD) FLT3 mutations. Although PCR based assays are predominantly utilized for molecular detection of mutations/translocations in AML, the field is moving toward a more rapid, robust and sensitive method. Given the importance of Minimal Residual Disease (MRD) in hematologic malignancies, particularly in AML, a standardized and highly sensitive NGS assay is needed for the detection of in FLT3-ITD mutations to enable and guide clinical and therapy decisions during the patient journey.
Rethinking the Companion Diagnostic Deal Structure to Benefit All Stakeholders
The standard Rx-Dx partnering model does not maximally benefit all parties (pharma company, diagnostic company, payer, physician, patient). It exposes both the pharma company and diagnostic developer to risk they cannot control, and may disincentivize the best product from reaching the market. How can diagnostic companies take more responsibility (and risk) for development- and reap the rewards in the market? We will discuss restructuring the traditional companion diagnostic deal, how diagnostic companies can consider a ‘post-companion’ approach, and how aligning incentives can benefit patients, payers and physicians.
The evolving role of biomarkers in immuno-oncology, technological innovations, and considerations for an IVD
Head of Diagnostics
Precision medicine continues to transform treatment paradigms through development of new biomarkers in the interpretation of clinical data. Immuno-Oncology biomarkers, such as PD-L1, and emerging ones, such as tumor mutation burden (TMB) and GEP, may help optimize treatment decisions, individually or in combination. New technological innovations offer the capability to further develop this field. The advancement of increasingly complex biomarkers also brings a need for advanced diagnostic tools. The evolving role of biomarkers in the field of immune-oncology and considerations for a future IVD will be discussed.
The Immunoassay if Thymidine Kinase 1 – A Liquid Biopsy of Cell Proliferation: Its Application in Oncology Drug Discovery and Development
AroCell, PLATINUM SPONSOR
Thymidine kinase 1 (TK1) is a salvage pathway enzyme involved in DNA precursor synthesis and its expression is cell cycle regulated. TK1 is up-regulated as a result of DNA damage and released from dying cells during un-regulated cell proliferation. TK1 has been widely used to study hematological malignancies but little has been published on its use as a biomarker in in-vitro models of malignancy and drug development.
The purpose of this study was to evaluate the application of changes in TK1 levels in an in-vitro culture of leukemic cells as a parameter of drug effects and response using a novel TK1 immunoassay- the AroCell TK 210 ELISA
The effects of Doxorubicin (DOX), an anthracycline drug that is an effective anti-neoplastic drug for both hematological and solid malignancies, were studied on CEM lymphoblastic cells.
Ensuring the rapid and reliable delivery of test results
Senior Genomics Liaisons, Regional Trainer
Molecular diagnostic testing is now an indispensable tool in optimizing outcomes in oncology. As the technology enabling the identification of therapeutic targets has advanced, the infrastructure required to deliver test results to clinicians has fallen behind. Test results are frequently delayed not by laboratory processing but rather by delays in ordering tests and by lengthy insurance prior authorization processes. Hospitals and laboratories spend millions of dollars to optimize molecular diagnostic workflows only to have results delayed by non-laboratory factors. By placing a focus on the ordering and insurance processing infrastructure, the full benefit of those investments can be realized in the timely delivery of results to clinicians. In doing so, delays in treatment can be avoided. Achieving this goal requires the constant monitoring of metrics related to order placement and insurance processing as well as the regular review of those metrics by all parties involved. Real time reporting of estimated release of results (considering insurance authorization) should be incorporated into these plans to allow clinicians to optimize patient scheduling.
Connecting Community Clinics and Patients with Biomedical Research Worldwide
Lakeside Life Sciences, DIAMOND SPONSOR
This presentation will explore the benefits of enrolling patients in community centers during clinical studies for precision medicine. And the effect patients will have on driving precision medicine to their family and friends. We will focus on methods to shorten the timing and decrease the cost to initiate and manage clinical studies. As well as discussing the commercial importance of doing research in rural and community clinics. And most importantly how this process will help patients drive the implementation of precision health on a larger scale. Precision health is a great buzzword, but how do we bring it to the world, and create healthier communities. Our objective will be to provide a clear and simple primer for current routes of enrolling patients into clinical studies, highlight the obstacles that need to be overcome, and to propose alternative strategies to ensure high numbers of enrolled patients, greater involvement of healthcare professionals, and greater utilization by community providers to help the patients that are ready for healthier lives.
We will begin with a discussion of various modes of enrolling patients for Precision health clinical studies:
Why do we always focus on Academic Centers?
How do we include more Patients?
Why aren’t Community and Rural centers participating in clinical studies?
We will outline the current clinical research paradigm:
Multiple IRB approvals
Lengthy Informed Consent Forms
Endless contract negotiations
We will describe the Community Provider and patient needs:
Is precision health being used outside of Academic Centers?
What do local providers need?
What is being treated in a community setting, and where is precision medicine needed. (primary care, family physicians, chiropractors, nutritionists, etc…)
Many recent publications have addressed an array of issues about clinical study enrollment numbers, and the implementation of companion diagnostics and precision medicine. We will discuss alternatives to not only increase enrollment, but discover real patient needs, and strategies to expand precision health to more than diagnostics that are companion to immunotherapies.
Why is it so hard to enroll patients?
Why do so few patients enroll in clinical studies?
How does research in a community setting help patients receive better care?
How can we expand precision health to include a more holistic picture of wellness through community-based care, that starts with research?
By creating well thought out clinical trials that involve true cross sections of America’s patient populations, and expanded our view of what precision health really is, we will:
Bring health out of the offices of CEO’s and put it back in patients’ hands
Involve patients more effectively
Gain patients trust back
Redefine our currently failing health system
Provide needed income to failing community hospitals
And most importantly help people live lives rich in health and wellness.
Companion Diagnostics in Immuno-Oncology: Global Commercial and Partnership Considerations
Senior Vice President
Boston Healthcare Associates
The testing paradigm in immuno-oncology is growing increasingly complex, moving beyond PD-L1, to include mismatch repair, microsatellite instability, tumor mutational burden, and others. The presentation will highlight key commercialization considerations for drug and test innovators, including balancing test access and quality, and embedding CDx global commercial considerations in pharma and diagnostic company partnerships
Stroma Liquid Biopsy™ – Blood-based Biomarkers To Monitor Stromal Conditioning In Cancer
Vice President, Business Development
Biotech Support Group
Tumors are more than simply a collection of immortalized cells. The supporting microenvironments or stroma also contributes to pathogenesis. Because of this, tumor characterization cannot be fully characterized solely through the tumor cell genome – the current emphasis of liquid biopsy platforms. As tumors are more than just proliferating cells, understanding cancer must take recognition of the multiple cell types and networks of proteins dynamically interacting in tumorigenesis. For this purpose, we have identified dysregulated serum Complement, Coagulation, and Acute-Phase Inflammation sub-proteomes associated with cancer.
This rewiring of the blood circuitry is measurable even at early stages of cancer, for many if not most primary tumors. The special significance of this profile is that dysregulation in these biomarkers is categorically intertwined with the most rudimentary needs of cancer: space, nutrients and immune evasion. Moreover, the changes within the panel of 13 proteins occur within an interdependent network of cascading proteolytic events. Because proteolysis is irreversible, molecular regulatory systems must control aberrancies, the most distinguished being a family of protease inhibitors known as SERPINs.
Although SERPINs circulate in a variety of functional on/off sub-forms, conventionally they are observed and reported in aggregate (i.e., ELISA). As a result, their influence on disease is missed. Using assays that directly assess SERPIN function, we now have evidence that there is an imbalance of functional SERPIN sub-forms in the cancer population. Such potentially transformative information supports the benefits of Stroma Liquid Biopsy™ biomarkers: all being highly observable, most of relative high abundance in serum and measurable by a variety of proteomic platforms; all being highly differentiated – many severely, in the cancer population, and very stable in the normal/healthy population; and all linked to the systemic interconnections between three key inflammatory pathways, many of which cannot be monitored by antigen presentation alone.
By using blood-based biomarkers, our collaborators will gain invaluable information central to understanding how individuals are uniquely predisposed to cancer, how individuals uniquely adapt to the presence of cancer anywhere in the body, and how individuals uniquely respond to medical intervention.