NEW YORK – International liquid biopsy test developer Datar Cancer Genetics plans to pursue regulatory US Food and Drug Administration clearance over the next two years for its brain cancer early detection assay, which was recently shown in a small real-world study to diagnose malignant brain tumors with high accuracy.
In the meantime, India-headquartered Datar is focusing on research studies to aid its regulatory journey and intends to expand the lab services it offers in the US from its lab facility in North Carolina in the coming months.
Currently, there are no rapid and simple blood tests to help diagnose brain cancers. Approximately 25,400 malignant tumors of the brain or spinal cord were diagnosed last year in the US, according to the American Cancer Society. Malignant brain tumors are typically composed of a cell type called glia, while nonmalignant brain tumors are often composed of other cell types or metastatic cells from primary epithelial malignancies.
Biopsies and surgeries are the standard of care and are used for diagnosis as well as pathological and molecular characterization. But, since both of these approaches require drilling into the skull and removing tissue from the brain, tumors in what neuro-oncologists call eloquent areas — sites with defined and important functions — present a challenge, as any lesions could result in disability.
Datar Cancer Genetics hopes to change that with its TriNetra-Glio test. Vineet Datta, the firm's executive director, said in an email that Datar has been developing circulating tumor cell (CTC) technology for the past eight years, and technology specifically to capture and detect circulating glial cells shed from brain tumors since 2019.
The firm's test is intended to determine malignancy of brain tumors by capturing and profiling circulating glial cells in blood. It uses a proprietary enrichment medium to selectively induce programmed cell death in nonmalignant cells, followed by immunocytochemistry.
Because glia are non-neuronal cells that mostly serve to insulate and protect the brain and form the blood brain barrier, the presence of any glial cells in blood indicates malignancy, Datta said. These cells are characterized as ones that stain for the glial markers OLIG2 and GFAP, but not for the markers CD45 and cytokeratin.
"Through this technology, we aim to have diagnosis of inaccessible tumors become possible, through a risk-free and patient-friendly blood test," Datta said.
Last year, Datar's test obtained breakthrough device designation from the FDA. Its early-stage breast and prostate cancer detection tests have also previously been given this designation from the FDA, which is intended to speed up the process of garnering regulatory clearance.
In a study published last year in the International Journal of Cancer, researchers from Datar and Imperial College London validated TriNetra-Glio in a blinded cohort of samples in a real-world setting, showing that it is highly specific for glial cancers and able to detect multiple grades and subtypes — including gliomas, astrocytomas, oligodendrogliomas, oligoastrocytomas, and glioblastomas — irrespective of gender and age. Overall, the test was evaluated in four clinical studies, and compared to gold standard histopathology of tumor tissue, it showed 100 percent specificity for detecting glial malignancy and 99.4 percent sensitivity in differentiating glial malignancy from nonmalignant brain tumors, brain metastases from epithelial malignancies, non-glial subtypes of central nervous system malignancies, and healthy tissue.
"To our knowledge, this is the first time a CTC-based technology is being utilized for a diagnostic stratification of brain tumors," Datta said, adding that the performance characteristics of the CGC-based test "support its clinical utility for diagnostic triaging of individuals presenting with intracranial space-occupying lesions."
There are downsides of using a CTC approach for gliomas, as opposed to extracellular vesicles or cell-free DNA, RNA, or miRNA, according to a 2021 review of glioma liquid biopsy published in the journal Cancers. For example, these cells are rare and difficult to isolate, with no established standards, and the CTCs may not be representative of the whole tumor.
However, compared to having brain surgery, there will likely be cost and time advantages to TriNetra-Glio, and patients may be more comfortable with noninvasive testing. Datar and its Imperial College London collaborators noted in their IJC study that patients who are extremely ill or have comorbid conditions can also be imperiled by surgery or biopsy, with risks including pain, hemorrhaging, swelling, and potentially fatal infection. Since many patients have so-called benign or borderline tumors, obtaining the same information noninvasively could be an improvement.
Robert Eibl, a coauthor of the review and former cancer researcher at the German Cancer Research Center (DKFZ), said that "any test which can detect brain tumor-derived cells at a high sensitivity in the blood should have some major impact."
However, Stephen Bagley, section chief of neuro-oncology at the University of Pennsylvania, said the primary value of the test would be in cases with both diagnostic uncertainty as well as a high surgical risk, even for a biopsy.
"With modern MRI technologies in high-volume centers, diagnosis of a glial malignancy can often be made based on imaging alone," Bagley said in an email, adding that true uncertainty about whether a tumor is a brain metastasis or a CNS lymphoma, for example, only occurs in a minority of cases.
Furthermore, tissue samples from glial neoplasms is needed to determine the type and grade of glioma and to perform molecular profiling, so "even if the blood test can tell us we are dealing with a glial malignancy, we still need to get tissue in almost all cases," Bagley also said.
Still, for cases where surgeons might be hesitant with biopsy, TriNetra-Glio could have value, Bagley suggested, although he also noted that even in these cases imaging results often provide enough information for neuro-oncologists to determine the type of tumor.
Datar's Datta noted that glial tumors such as diffuse intrinsic pontine glioma (DIPG) are difficult to biopsy and that these biopsies are associated with significant risk. "The goal is to position TriNetra-Glio as a noninvasive triage tool prior to, or as an alternative to, a tissue biopsy to improve patient safety," he said, adding that further studies are planned to expand the scope of the solution.
Similar tests have also been described in the literature. For example, physician-scientist Natalia Malara and her team at the University Magna Graecia in Catanzaro, Italy, have developed a multicancer detection assay that includes detection of circulating cells from gliomas, with CTCs recognized by immunostaining with GFAP as well as a marker called S-100.
"Our test is able to distinguish circulating non-hematological cells derived from malignant gliomas from nonmalignant brain tumors and metastases derived from primary epithelial malignancies through a traditional immunostaining approach," Malara said in an email. In a proof-of-concept study, the group showed that 14 days in cell culture using its methods could be combined with cell staining and flow cytometry to determine whether the expanded cell population was proliferative. In Molecular Cancer last month, the researchers also showed that combining the method with a supervised machine learning model led to 100 percent sensitivity, and 95 percent specificity in liquid biopsies using a sample of 72 healthy controls and 204 cancer patients, including eight with glioblastoma.
Another similar test, called Dxcover Brain Cancer liquid biopsy, uses infrared spectroscopy combined with a diagnostic algorithm in a noninvasive blood test.
In Bagley's opinion, a larger and even more exciting field than post-imaging liquid biopsy is using it to molecularly profile brain cancers and potentially serially monitor them during and after treatment. He recently reviewed this topic, noting as well that liquid biopsy of cerebral spinal fluid is another exciting and emerging field.
Commercialization
Datar, whose corporate offices are in Nasik in the Indian state of Maharashtra, intends to pursue FDA approval for TriNetra-Glio over the next 18 to 24 months, Datta said.
The company's prior US distribution strategies involved a $250 million partnership with Artemis DNA, announced in mid-2022. Artemis, also known as ApolloMDx, was a full-service CLIA/CAP lab with facilities in Houston and Irvine, California, and was to distribute Datar's CancerTrack and TruCheck Pragma tests in the US.
But in mid-2023, Artemis executives were charged with submitting $142 million in fraudulent Medicare claims, $95 million of which were paid out by Medicare, according to the US Department of Justice. In court filings, the DOJ said the claims were induced through kickbacks and bribes and were not medically necessary nor eligible for reimbursement. Artemis now appears to be no longer operating.
Datta said Datar became aware of all this through media reports, and declined to comment on the ongoing legal issues.
Datar is now following an independent path of commercial and research outreach in the US, Datta said, with efforts being led from the group's third and most recently opened global lab facility in Raleigh, North Carolina.
"We hope to have the US facility run commercial samples later this year," said Datta, adding the firm is "committed to our formal US regulatory pursuits."
Overall, Datar currently offers its tests in more than 40 countries and plans to expand to more than 50 countries in 2024.
In the past three years, Datar has scaled up its UK operations with a UKAS-, CAP-, and CLIA-accredited lab outside of London that offers commercial and research services. Datta said that TriNetra-Glio is available internationally as a lab-developed test.
In late 2023, Datar also partnered with London-based Cromwell Hospital to create a bespoke second opinion service and virtual care pathway for patients, Datta said, "offering a comprehensive discussion on integrating tissue and blood-based genomic solution outcomes into the cancer care pathway."
Datar also intends to explore integration of TriNetra-Glio into public health clinical care pathways in the coming years, Datta said.
And the firm is developing a technology for comprehensive, multi-analyte molecular analysis to help tailor treatment strategies for refractory, relapsing, and metastatic cancers.
"Our label- and organ-agnostic treatment strategies for such patients, based on an integrative, multi-analyte tumor analysis, capture in-depth information about the multilayered tumor interactome," Datta said. Targeted treatment has so far focused on DNA alterations, which leads to a clinically relevant outcome in only around 40 percent of patients, he said, adding, "clinical benefit is another matter." Datar described its comprehensive tumor profiling tool to improve treatment efficiency at the European Society for Medical Oncology annual meeting last year, he said, revealing more actionable characteristics for combining appropriate therapies. "We intend to share more data in this arena over the coming year."