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Novel Combination Cancer Therapy, Innovative Approach to Regional Cancer Care, Tissue-Agnostic Drug Approvals, Liquid Biopsy, and Metabolomics Featured on Morning of Day 3 of Precision Medicine World Conference (PMWC) 2018

Track 1 (Patient-Centered Care) of Day 3 of the Precision Medicine World Conference (PMWC) 2018 began with a presentation by Ron Levy (photo), MD, Professor and Chief, Division of Oncology, Stanford University School of Medicine. Over a decade ago, Dr. Levy developed the first FDA-approved antibody for the treatment of cancer, rituximab, which is now used for every lymphoma patient, either as a standalone treatment on in combination with other therapies. Dr. Levy’s talk on this day was titled “A Better Way to Trigger the Immune Response Against Cancer.” Dr. Levy outlined a new combination immunotherapy approach that is described in a January 31, 2018 Science Translational Medicine article (http://stm.sciencemag.org/content/10/426/eaan4488). In a mouse model, Dr. Levy’s group showed that intratumor injection of the combination of unmethylated CG-enriched oligodeoxynucleotide (CpG), a Toll-like receptor 9 ligand (TLR9), and anti-OX40 antibody led to shrinkage of distant tumors and long-term survival of the animals, even in a stringent spontaneous tumor model. Low doses of CpG injected into the tumor induce the expression of OX40 on CD4+ T-cells in the microenvironment of the tumor. An agonistic anti-OX40 antibody can then trigger a T-cell immune response that is specific to the antigens of the originally injected tumor. TLRs are components of the innate immune system that recognize molecular patterns on pathogens. In mice, the combination of CpG, TLR9, and anti-OX40 was shown to cure multiple types of cancer and to prevent spontaneous genetically driven cancers. Dr. Levy noted that one of the most spectacular results was seen in a model of spontaneous breast cancer where the combination treatment eliminated the cancer from all ten mammary glands in a very short time. Dr. Levy described this result as an “amazingly powerful and rapid effect.” The next speaker was Edward Kim, MD, Chair, Solid Tumor Oncology and Investigational Therapeutics, Levine Cancer Institute. The Levine Cancer Institute has more than 25 cancer care locations throughout the Carolinas and focuses on the person, not just the disease. Dr. Kim recently came to the Levine Cancer Institute from MD Anderson and he studies novel targeted agents in the treatment and prevention settings, and has expertise in lung and head and nceck cancers. In his PMWC 2018 presentation, Dr. Kim described Electronically Accessible Pathways (EAPathways), an electronic pathway system that helps guide patient care and empowers providers. He also spoke on the Institute’s Biospecimen Repository-LiNK system, which coordinates specimen collection and matching genome results to clinical trials. Dr. Kim’s presentation was titled “Implementation of Precision Medicine and Pathways into Regional-Based Patient Care.”

He has noted that, recently, Levine Cancer Institute faculty physicians across North Carolina and South Carolina “have joined together in close-knit, disease-specific sections to develop EAPathways for community-based oncologists system-wide that outline clinical treatment pathways, palliative care and social work pathways, and importantly, the real-time availability of clinical trials. The sections have put together pathways for more than 15 solid tumors. Pathways have also been developed by sections for hematologic malignancies, including acute chronic myeloid leukemia.” (https://www.carolinashealthcare.org/documents/cancer/Updates-in-Cancer-v... page 5)

Available to clinicians via the Carolinas HealthCare System intranet, the EAPathways software application allows physicians 24-hour access to the preferred treatment pathways for a patient with a particular cancer type. All clinical trials are displayed prominently alongside corresponding pathways and trial enrollment is highly encouraged.

Dr. Kim believes that the advantages of EAPathways to patients and physicians are plentiful. First and foremost, physicians will have real-time access to open clinical trials. Importantly, the EAPathways software will provide general community oncologists with a set of preferred treatment pathways, enabling them to provide the same clinical care options as a specialty oncologist.

Providing oncologists in rural locations across the Carolinas with the EAPathways will largely standardize cancer treatment for patients of Carolinas Health Care System and afford them, closer to home, the same quality health care they would receive at a larger, metropolitan cancer facility.

TISSUE-AGNOSTIC DRUG APPROVALS

Later in the morning, PMWC program chair George Sledge, MD, Professor and Chief of Medical Oncology at the Stanford University Medical Center, spoke on “Tissue-Agnostic Drug Approvals.” Dr. Sledge noted that on May 23, 2017, the FDA announced approval of pembrolizumab, which is targeted against solid tumors that have been shown to be mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H), in individuals who have progressed after prior treatment and who have no satisfactory alternative treatment options. The FDA generally approves drugs for cancer on the basis of a therapy studied in a clinical trial with patients with a particular tumor types. As reported in Medscape on June 19, 2017 (https://www.medscape.com/viewarticle/881609), “Although the FDA has approved drugs based on a biomarker, these drugs have generally been approved for specific biomarker-positive tumor types," said Dr Steven Lemery, MD, FDA's lead medical officer for regulatory considerations regarding tissue-agnostic development. "With the new pembrolizumab approval, patients with MSI-H can now benefit regardless of whether they have colorectal cancer, endometrial cancer, gastric cancer, pancreatic cancer, or any other tumor type. With this approval, the existence of the biomarker in essence defines the disease rather than the organ defining the disease."

WHAT IS THE CLINICAL UTILITY OF LIQUID BIOPSY?

Next in Track 1 was a panel discussion titled “What Is the Clinical Utility of Liquid Biopsy. The session was moderated by Atul Sharan, President & CEO, CellMax Life. The panelists included Richard Schilsky, MD, Senior VP and Chief Medical Officer, ASCO; Bruce Patterson, MD, Founder & CEO, incellDx; and Yatin Mundkur, CEO, Cellworks. Moderator Sharan is a trained engineer who founded CellMax Life after his wife had been cleared of breast cancer in a mammogram and then, just weeks later, was diagnosed with breast cancer via additional testing. His wife is fine today, but this experience, coupled with his increasing knowledge of cancer, convinced Sharan of the paramount importance of early diagnosis in cancer. Early detection can lead to earlier treatment and much increased chances of treatment success. CellMax seeks to provide globally affordable early cancer detection blood tests.

The company has developed a proprietary platform-microfluidic chip, antibody, and imaging software- that Sharan believes has enabled CellMax to be the only company to overcome the “intractable” challenge of detecting rare CTCs in pre-cancer and early-stage patients, when cancer can be most successfully treated. Once CTCs are captured via the CellMax platform, the company can analyze the CTCs comprehensively for multiple clinically relevant biomarkers—DNA, and also RNA, protein expression, and methylation. The CellMax platform can also be used in in the capture and analysis of circulating tumor DNA (ctDNA) to enable early detection of cancer.

A January 16, 2018 ASCO press release (https://www.asco.org/about-asco/press-center/news-releases/liquid-biopsy...) reported results of a Taiwan study using a CellMax assay to detect CTCs in screening for colon cancer. The testing yielded specificity values of 97.3%, indicating a very low (less than 3%) probability of a false-positive result. The study results further showed that sensitivity ranged from 77% for detection of CTCs in pre-cancerous lesions, to 87% for stage I-IV cancers. The researchers also calculated the accuracy of the results, which takes into account both sensitivity and specificity, and found that the accuracy of the test was high and ranged from 84% to 88% between pre-cancerous and cancerous samples. The accuracy of this test was superior to that of fecal occult blood testing (FOBT).

In a press release issued following the PMWC 2018 panel discussion, Sharan was quoted as saying, “"Early detection is perhaps the only real cure for cancer. To be effective, tests for early cancer detection need to be non-invasive, easy, highly affordable, and accurate. The CellMax CTC blood test meets all of these requirements," said Atul Sharan, co-founder and CEO of CellMax Life. "With the use of tumor specific antibodies, the CTC blood test can identify the origin of major solid tumors. It is therefore a pan-cancer platform for cancer detection, therapy selection, and treatment effectiveness monitoring." (http://www.prweb.com/releases/2018/01/prweb15132068.htm).

Dr. Patterson emphasized the importance of going to single cells for the analysis of CTCs in liquid biopsy. Dr. Patterson’s company, incellDx is a single-cell diagnostic company committed to advancing precision medicine by offering transformative diagnostic and prognostic clinical patient information based on an innovative technology platform that enables simultaneous cell classification and single-cell analysis of proteomic and genomic biomarkers. The incellDx technology combines a unique multiplex RNA in situ hybridization method called Simultaneous Ultrasensitive Signal-amplified Hybridization In Situ (SUSHI) with a novel, cell-based instrument capable of quantifying multiple proteins and molecular biomarkers inside intact cells. This allows protein and gene expression to be measured by distinct cell type which aids both diagnosis and disease localization. The company currently has more than 30 issued and pending patents. The technology is ultra-fast, inexpensive, highly reproducible, and able to perform complex molecular testing without DNA extraction or amplification.

Panelist Yatin Mundkur has launched businesses in medical diagnostivs, technology, and communications. His current company, Cellworks, assists interpretation of heterogeneity in a patient’s tumor genomic profiling using computational mathematics and bio-simulation to create the patient’s genomic profile, and to understand the biochemical molecular pathways and disease phenotypes for effective clinical outcomes. The company’s reports provide the physician with actionable suggestions, each with a transparent causative rationale. Cellworks provides three products for oncologists to assist in treating patients previously diagnosed with specific oncology indications. Cellworks translates the molecular and genomic knowledge of the patient’s tumor into actionable interventions, after analyzing the effectiveness of FDA-approved drugs on the patient’s tumor.

In a June 3, 2017 Reuters article on GRAIL’s early success with an ultra-sensitive detection of DNA traces of cancer in the blood, ASCO CMO Dr. Schilsky was quoted as saying, “Basically, what they’re showing is that they can detect in blood the majority of the same mutations that they can detect in tissue of patients with advanced cancer.” Dr. Schilsky said the study is a first step in validating the test, adding that diagnosing early-stage cancers from a blood test “is a very high hurdle.” (https://www.reuters.com/article/us-health-cancer-biopsy/grail-passes-ear...).

IMPROVING RARE DISEASE DIAGNOSIS WITH METABOLOMICS

In a later presentation, Sandra Merkel-Dejames, PhD, VP, Metabolon Inc., spoke on “Improving Rare Disease Diagnosis with Metabolomics.” Today, the company believes that the ability of its metabolomics technology to impact human health is becoming more compelling than ever as the promise of precision medicine rapidly approaches a reality. On a certain level, all diseases are metabolic; there is almost always a physiological manifestation that is reflected in the patient's metabolites. While genomics may reveal disease risk, Metabolon’s Precision Metabolomics™ technology may provide a snapshot of the current state of health and actionable information to advance clinical decision-making.

The foundation of the Precision Metabolomics technology lies in Metabolon’s extensive, authenticated biochemical reference library. The biochemical library was developed by analyzing more than 3,000 pure reference standards of known metabolite structures with the company’s LC/MS methods and cataloging all the ions that were produced.

With over 15 years of experience and more than 7,000 completed studies, Metabolon’s library now includes known and novel metabolites. The company believe that this robust, ever-expanding library offers the most comprehensive metabolomics coverage available and allows for rapid metabolite identification for subsequent statistical analysis. To automatically filter extraneous, noise-producing data, the company’s mass spectrometers are connected by proprietary software to this rigorously built chemical library.

Monitoring patients' health, diagnosing disease, and making the best treatment decisions for an individual based on their unique characteristics, including their metabolomic profile, enables healthcare providers to provide the right care, to the right patient, at the right time. Streamlining healthcare providers' ability to understand the basis of an individual's health, disease and treatment response using a single metabolomic-based test will enhance their ability to achieve this objective. Metabolon believes it is uniquely positioned to deliver such insights quickly and accurately using our patented metabolomics-based technology and clinically validated tests.

Dr. Merkel-Dejames noted that Metabolon's META IMD™ is a novel test for assessing up to 70 inherited metabolic disorders (IMDs) using one small biological sample. The company’s growing precision medicine pipeline is focused on tests that provide metabolic insights that aid in diagnosis and promoting and maintaining wellness.
Metabolon’a industry-leading metabolomics technology platform and data are generating new insights into inherited metabolic disorders and other rare and undiagnosed diseases. The company’s platform is also being used by the world's top pharmaceutical companies, precision medicine innovators such as Health Nucleus and Arivale, and national and regional population health studies led by innovative research organizations such as the University of Cambridge.

Metabolon continuously evaluates new hardware and chromatography to advance its mission to provide the highest-quality metabolomics solutions and develop innovative precision medicine products. Presently, samples are processed using four ultra-high-performance liquid chromatography/tandem accurate mass spectrometry (UHPLC/MS/MS) methods. This highly precise hardware generates the raw data that Metabolon’s proprietary software filters and processes to create actionable insights. All systems are operated in a rigorously controlled environment to remove as much noise from the process as possible and guided by SOPs to standardize results.

(Photo credit: Rosalyn Lee, PMWC).

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