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Exosome Testing Year in Review: Commercial Prospects Improve for Liquid Biopsy Technique


NEW YORK (360Dx) – During the past year, researchers developing diagnostic tests that detect and analyze disease markers within exosomes reported progress with creating more promising techniques to isolate the exosomes prior to their measurement by liquid biopsy test systems. In so doing, they have pushed their exosome diagnostic tests closer to commercialization

Such blood-based tests, which detect DNA, RNA, and proteins that may be associated with disease, can be applied noninvasively and more frequently without causing as much patient discomfort as tissue biopsies. They can provide a perspective on the status of a tumor as disease progresses and could also be used to track a tumor's emerging resistance to a cancer drug.

Tony Jun Huang, a professor of mechanical engineering, materials science, and biomedical engineering at Duke University's Pratt School of Engineering said in a recent interview that liquid biopsy tests, such as those that use exosomes, circulating tumor cells (CTCs), and cell-free DNA (cfDNA) "have the potential to revolutionize the early detection of cancer," provided the tests "meet stringent criteria for sensitivity and specificity."

"However, exosomes have some unique features and advantages over CTCs and cfDNA, which make them ideal liquid biopsy candidates," he said.

Exosomes — small double-lipid membrane vesicles that are secreted from cells — are stable and are capable of preserving content through multiple freeze and thaw cycles, he said, adding that they are also highly abundant with concentrations ranging from thousands to billions per microliter.

Still, the field of exosome testing "needs better ways to separate exosomes," he said. "The development of an automated, high-performance exosome isolation platform would greatly improve the possibility to use exosomes as a biomarker in cancer biology and clinical oncology, especially in the field of early cancer detection."

Waltham, Massachusetts-based Exosome Diagnostics has already taken exosome technology to clinical use and begun marketing tests for lung and prostate cancer. In 2016, the firm launched its ExoDx Prostate IntelliScore test (EPI) through the company’s CLIA-certified laboratory in Cambridge.

EPI is a laboratory-developed urine test that looks for three exosomal RNA biomarkers expressed in men with high-grade prostate cancer to help in the biopsy decision-making process. In July, Exosome Diagnostics closed a $30 million Series C financing, led by Tiger Partners and Forbion Capital Partners and said that it would use the funds to support the commercial expansion of its EPI test. It noted at the time that the financing would also help sustain commercialization plans for other diagnostics in the oncology market and development of tests in other areas, such as neurodegenerative diseases, transplant rejection monitoring, and cardiology.

This past August, the firm announced an agreement with CareFirst Blue Cross Blue Shield to collaborate on clinical studies aimed at driving health plan coverage for molecular diagnostic products.

The deal marked the first that CareFirst had signed as part of its HealthWorx program under which the payor works with early-stage companies to generate evidence demonstrating the clinical utility of their tests and technologies in order to accelerate the coverage determination process.

CareFirst's partnership with Exosome has resulted in a completed 500-patient evidence development study of the test.

Despite Exosome's example, the effort to develop exosome-based diagnostic tests is a recent development, though many research groups are investigating the biological functions of extracellular vesicles, Yoon-Kyoung Cho, a professor of biomedical engineering at Ulsan National Institute of Science & Technology (UNIST), South Korea, told 360Dx.

To measure and analyze exosomes, researchers need to properly isolate them from urine or blood and separate them from particles that are not diagnostically interesting, They have been using an established method, ultracentrifugation, in isolating exosomes, but according to researchers, the approach has some drawbacks in clinical use.

For example, a recent survey found that 56 percent of researchers use ultracentrifugation for isolating exosomes, Duke's Huang said, but "[w]hile ultracentrifugation has proven to be an effective method for isolating exosomes, it is time-consuming, expensive, [and] demanding [because] highly training personnel are needed, and [it] has limited purity and yield."

High centrifugal forces used in ultracentrifugation have been shown "to cause exosome fusion, promote coagulation, and alter the properties and functions of the exosomes that are measured during downstream analysis," he added.

As an alternative to ultracentrifugation, Cho and her colleagues are developing a liquid biopsy-based lab-on-a-disc that incorporates centrifugal force and nanoporous membranes in isolating and identifying extracellular vesicles that carry potentially important biomarkers of cancer in urine.

Also, Huang and his colleagues at Duke are working with the Massachusetts Institute of Technology, the Magee-Womens Research Institute at the University of Pittsburgh, and Nanyang Technological University to develop a point-of-care prototype that combines acoustics with microfluidics to separate the exosome particles from blood, accelerating the potential for future liquid biopsy tests that could detect a broad range of medical conditions.

They are developing the device for early detection of cancers, neurodegenerative diseases, cardiovascular diseases, kidney disease, and liver disease.

In a study published in the Proceedings of the National Academy of Sciences in August, the researchers described a device that uses a combination of microfluidics and sound waves to isolate the exosomes from blood.

They hope to eventually use the technology as the basis for a portable device that could analyze patient blood without requiring lab processing and without requiring ultracentrifugation.

Meanwhile, researchers at Harvard Medical School and the Massachusetts General Hospital Center for Systems Biology are developing a point-of-care, exosome marker-based diagnostic test that can differentiate cancer exosomes from normal exosomes. Lead investigator Hakho Lee told 360Dx in April that the test developed by his group at the Center for Systems Biology, called the integrated magnetic-electrochemical exosome test, or iMEX for short, could be ready for licensing in 2018.

The test integrates both vesicle isolation and detection into a single platform and eliminates the need for ultracentrifugation.

Lee said that his group envisions that the type of tests that are now done in a doctor's office or small clinic could be done by analyzing exosomes with an affordable point-of-care device, such as an iMEX POC test. The research group is developing the platform alongside a second exosome-based diagnostic test, nPLEX, which is suitable for high-volume applications. Exosome Diagnostics licensed nPLEX in December 2016.

A separate exosome nanoplasmonic assay is being designed specifically to fit into clinical workflows by researchers at Harvard Medical School and Massachusetts General Hospital. The group is taking aim at high-throughput detection of pancreatic ductal adenocarcinoma, an aggressive and often inoperable form of pancreatic cancer.

In its sensitivity and specificity, the Harvard-MGH test outperformed the best-established blood test currently available, which uses cancer antigen 19-9 as a PDAC tumor marker, said Cesar Castro, director of the cancer program at MGH Center for Systems Biology, and a coauthor of a published research study that investigated the test in clinical use. He noted that the new assay may enable earlier detection for PDAC, a condition that is often untreatable.

Elsewhere, Lonza announced in May that it had acquired HansaBioMed Life Sciences, an Estonian exosome research tool developer, and invested in Exosomics, an Italian molecular diagnostics startup. The Swiss biopharmaceutical company said both deals are focused on developing new therapeutic and diagnostic applications based on exosomes.

In a statement, Uwe Gottschalk, chief technology officer for Lonza's pharma and biotech segment, said the company sees opportunities for using exosomes-based assays in cancer diagnostics, and offered that the cell-derived vesicles "could become the next generation of cell-free therapies in regenerative medicine."

In October, a team of industry players and a Japanese government agency announced a collaboration that would leverage exosomes to improve cancer diagnosis and treatment.

The collaboration is between the National Cancer Center Japan, JVCKenwood, Sysmex, and Daiichi Sankyo, and aims to detect cancer-specific exosomes from patients' blood. As part of the deal, JVCKenwood will leverage its exosome measurement device to build technologies for detecting cancer-specific exosomes. Sysmex will evaluate the exosomes, applying its proprietary gene and protein measurement technologies for clinical use.

The National Cancer Center Japan and Daiichi Sankyo will leverage exosome measurement data to improve the diagnosis and treatment of patients.

Exosomes are not alone among circulating packets that give useful information for cancer diagnostics.

In a poster published in Nature Reviews Clinical Oncology, the authors noted that DNA released from tumor cells into the circulation can not only be detected in the blood of patients with cancer but they can also provide information about how the cancer is evolving on a molecular level, and miRNAs "have good stability and are being explored as biomarkers that enable screening and/or early detection."

Huang noted that many studies have linked the number of CTCs with diagnostic and prognostic outcomes for many different types of cancers, but CTCs "are extremely rare," typically occurring in volumes of 1 to 100 cells per 1 milliliter. They also tend to be fragile with CTC apoptosis beginning early after separation from the tumor of origin, he said. cfDNA is more abundant than CTCs, but one of its main drawbacks is its relatively short half-life of 20 minutes to two hours before it is cleared from circulation, Huang said.