PMLS Virtual Series 2021 – Precision Oncology Spring

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March 30, 2021

10:00-10:55am EST

The Value of Adding RNA Sequencing to Biomarker Strategy

Joel Dudley, PhD, MS, Chief Scientific Officer, Tempus

Current approaches to the molecular characterization of cancer are highly variable, with a collection of methods available for genetic profiling and protein-level assessments. High-throughput, next-generation sequencing is one such method that has recently been shown to improve treatment options and diagnosis for cancer patients through different bioinformatics processing algorithms and pipelines. While sequencing DNA is a valuable method for assessing mutation status across multiple genetic targets, it does not directly survey other mechanisms, such as epigenetics, which may profoundly affect tumor biology and have critical consequences for treatment decisions in oncology. Additionally, genetic regulatory events, such as altered splicing, may also lead to alterations in gene expression and  often inform diagnosis, prognosis, and/or treatment more directly than DNA sequencing alone.

Consequently, next-generation sequencing of RNA has emerged alongside DNA sequencing as a technique to profile the tumor microenvironment and strengthen precision oncology. A particularly robust measurement for tumor expression  is whole-transcriptome sequencing (WTS), which can detect mRNA signatures and aberrations across the entire transcriptome. Multiple studies have demonstrated the benefits of RNA sequencing alone, and in combination with DNA sequencing, for cancer patients 1, but comprehensive platforms for WTS are still not widely available to patients or clinicians, and are yet to be incorporated into standard clinical care.

This virtual event will begin with an introduction in Tempus’ offerings including RNAseq, and then explore the benefits of using gene expression, fusions and splicing data for patient screening and dive into the future of RNAseq versus IHC for biomarker identification.

11:00-11:50am  EST

Panel Discussion

TBD

11:55-12:45pm  EST

Panel Discussion

TBD

12:50-1:10pm  EST 

Fireside Chat – Representative Sequencing for Whole Tumor Samples 

Nelson Alexander, PhD, Research Leader, Roche Sequencing Solutions; Samra Turajlic, PhD, MBBS, MRCP, Independent Group Leader, Francis Crick Institute; Consultant Medical Oncologist, The Royal Marsden NHS Foundation Trust

Researchers have long since known that tumors are heterogeneous. While the heterogeneity may not be defined by sharp, distinct boundaries, regions can be determined by cells in the tumor that have distinguishable morphologies and phenotypes. Not only can heterogeneity confound characterizing the tumor for diagnostic assessment, it can present difficulties in prescribing effective treatment strategies. Recently, a consortium of researchers published results on a proposed representative sequencing, RepSeq, protocol to quantify heterogeneity throughout the volume of tumors. The protocol allows for a more thorough assessment of distinguishable, spatially distributed regions throughout tumors.

1:15-1:45pm      EST

Building New Clinical Solutions for Personalized Oncology via Proteogenomics 

Mandy Paulovich, MD, PhD, Professor and Aven Foundation, Endowed Chair, Director, CLIA Targeted Proteomic Laboratory Clinical Research Division, Fred Hutchinson Cancer Center, Director, Clinical Research Proteomics Platform, Brotman Baty Institute for Precision Medicine

Personalized oncology aims to match each patient to a specific therapy based on the molecular characteristics of their tumor.  Currently, tumor DNA is sequenced, and genomics reports are given to physicians on tumor boards to help select targeted therapies for patients. While this approach has found success in extending the lives of subsets of patients, many patients do not respond to the selected therapy, and even those who do initially respond have a high chance of recurring as resistant disease.  Therefore, a deeper, more comprehensive readout of tumor biology is required in order to predict tumor phenotype with respect to drug response.

The majority of molecularly targeted therapies (e.g., kinase inhibitors, poly(ADP- ribose) polymerase (PARP) inhibitors, and therapies targeting immunomodulatory proteins) do not directly target the cancer genome but rather target proteins in cancer cells or the microenvironment. Thus, understanding and quantifying the expression of target proteins and their network throughout all phases of personalized oncology, from drug development to patient selection, are critically important.

This presentation will discuss the added value of proteogenomics over the current genome-driven approach to the clinical characterization of cancers and summarize current efforts to incorporate targeted proteomic measurements based on selected/multiple reaction monitoring (SRM/MRM) mass spectrometry into the clinical laboratory to facilitate clinical proteogenomics.  See also: Nat Rev Clin Oncol. 2019 16(4):256-268. PMID: 30487530

1:55-2:50pm      EST 

What Does the Future of CAR-T Hold? 

Moderator: Alessandra Cesano, MD, PhD, Chief Medical Officer, ESSA

Panelists: Adrian Bot, MD, PhD, Vice President, Translational Medicine. Kite, a Gilead Company; Lisa Butterfield , PhD, Vice President, PICI Research and Development, Parker Institute for Cancer Immunotherapy, Adjunct Professor, Microbiology and Immunology, University California San Francisco; Francesco Marincola, Global Head, Research, Kite, a Gilead Company

Chimeric antigen receptors (CAR) are fusion proteins engineered from antigen recognition, signaling, and costimulatory domains that can be used to reprogram immune cells to specifically target tumor cells expressing specific antigens. CAR-T cells-based treatments have demonstrated dramatic curative potential in a subset of patients with refractory B cell malignancies. However, current CAR-T cell therapy still faces several challenges, including suboptimal persistence and potency, impaired trafficking to solid tumors, local immunosuppression within the tumor microenvironment and intrinsic toxicity associated with the CAR-T cell products.

To overcome these challenges, additional genetic engineering of CARs combined with synthetic biology and the use of combinational therapy are currently being investigated to provide cellular immunotherapy with novel attributes necessary to overcome its hypo-functionality, trafficking issues, and the immunosuppressive forces in the TME. In addition, efforts to enhance the safety profile of CARs with better spatial and temporal control of their activity and persistence after deployment are also under investigation.

This panel discussion will  focus on recent strategies to improve the clinical efficacy of CAR-T cell therapy and other exciting CAR approaches currently under investigation, including CAR natural killer (NK) products.

2:55-3:45pm  EST

Will Cancer Screening be as Simple as a Blood Test?

Moderator: Michael Kolodziej, MD, Vice President and Chief Innovation Officer, ADVI Health

Panelists: Louis Jacques, MD,  Chief Clinical Officer, Senior Vice President, ADVI Health

Early diagnosis leading to improved cancer outcomes is a core tenet of medicine. This has been codified by the establishment of screening guidelines under the auspices of the USPSTF and the uniform, no cost coverage mandated by the ACA. Even so, screening has enjoyed less than universal adoption. The emergence of “liquid biopsy”, ie cf DNA sequencing in blood specimens, in cancer patients has generated excitement over the possibility that a similar technique could lead to early cancer diagnosis with attendant improved outcomes. We will review the state of the science and then discuss the regulatory and payer challenges that will face this exciting technology.