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Liquid Biopsy Effort Aims to Improve Diagnosis of Childhood Viral Lymphomas in Sub-Saharan Africa

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NEW YORK – Researchers and physicians hope that an effort beginning this month in Tanzania and Uganda will be able to successfully validate quicker and less invasive diagnostic methods for childhood lymphomas that are endemic in the region.

The initiative also aims to build the infrastructure and expertise needed to serve as a seed for future genomic test development and services in sub-Saharan Africa.

The program has been awarded £4.3 million ($5.5 million) from the UK's National Institute of Health Research (NIHR) along with £200,000 ($258,000) in seed funding from the Wellcome Trust and Global Clinical Research Fund. It was spurred by emerging research in the liquid biopsy space showing that viral DNA in patients' bloodstreams can be used to detect and diagnose virus-associated cancers.

Thus far, most of this research has been focused on efforts to create screening, early detection, and diagnostic tests for tumors that occur in the head and neck, including human papillomavirus (HPV)-associated tumors of the mouth and throat and Epstein-Barr virus (EBV) cancers of the nasopharynx.

For the new effort in sub-Saharan Africa, the target also involves EBV, but in this case, cancers that this infection seeds in the lymphatic system. Public health estimates suggest that about 90 percent of children who get these EBV lymphomas reside in sub-Saharan Africa.

University of Oxford director of molecular diagnostics Anna Schuh, who leads the project, said that the effort was proposed in response to a call from NIHR for proposals aimed at major global health issues, one of which was infection-related cancers.

With EBV lymphoma "we have a disease that is highly curable," Schuh explained. "It is a type of Burkitt's lymphoma, and over 90 percent of kids [can be] cured with very simple chemotherapy as long as they are diagnosed promptly, in the early stages of the disease."

Unfortunately, she said, prompt diagnosis is not happening in the regions in question. "At the moment, mortality … in most areas of sub-Saharan Africa [approaches] 100 percent."

Treatment is also free of charge in many countries in the area, she added, making the promise of rapid and widely deployable diagnostics even more acute.

Currently, if children in the area are definitively diagnosed, it is by traditional pathology — with a needle biopsy of a suspected tumor and follow-on analyses like IHC or FISH. But Shuh said that reaching a pathological diagnosis can be hard to establish because children will present with abdominal masses or with less obvious disease.

"Only 29 percent of hospitals with pediatric facilities have got a surgeon who can actually do a biopsy and there's not enough pathologists to perform the diagnostics robustly," she added. As a result, kids are treated mainly on clinical suspicion, which Schuh said is far from ideal.

"There are now increasingly studies that have been published from Malawi, from Rwanda, from various places, that show that clinical suspicion is not always correct. In fact, most of the time it's wrong. And that is because ... there's a whole range of childhood leukemias and lymphomas that you can't just diagnose by staring at the child at the bedside. You have to have proper pathology. And this is what the whole point of this [project] is — that we might be able to leapfrog [some of these hurdles] and go straight to cell-free diagnostics," she explained.

Schuh and colleagues at Oxford had previously done significant research on cell-free DNA sequencing in cancer. But the ideas behind the method they have developed for the EBV project in Africa were spurred from groundbreaking research published in recent years by Hong Kong University investigator Dennis Lo.

The test design that the group has developed for their lymphoma work is "a mixture of doing tumor sequencing and viral sequencing," Schuh said.  This combination approach can both differentiate EBV-associated Burkitt's lymphomas, based on the presence of EBV DNA, and detect potentially informative DNA mutations.

"We have to also bear in mind the cost of the sequencing, of course," Schuh said. "Ideally what we would like to do is a genome-wide approach, but what we have resigned to doing is sequencing bits of the human tumor, but the whole of the EBV genome."

The program that has been funded will stretch over four years, the first two of which are mainly focused on building infrastructure , but the ultimate goal is to nail down the most cost-effective method for diagnosis: either the liquid biopsy approach that Schuh and colleagues are developing or traditional pathology screening that involves tissue biopsies and immunochemical staining.

"It's designed as a before and after study, which means that after we develop the test and we've done the technical validation, we will essentially run with pathology for one year … with primary endpoint [being] the time it takes from the kids first presenting to the time it takes to get clinical report. And then in the next year … we will do exactly the same, but we will also do the liquid biopsy and see if it's faster or not. That's the primary endpoint."

Complicating this head-to-head comparison though, Schuh added, is the fact that comprehensive pathology services and expertise are currently in short supply in this region of Africa.

"We have 43 pathologists for 56 million people in Tanzania, for example … [so] … there is a there's a big need to create capacity," she said.

Reflecting this reality, a significant portion of the program will involve training and infrastructure development to allow for better standard pathology diagnoses, against which liquid biopsy can then be assessed. "This is not just a scientific study. We are actually trying to have a direct impact on patients outcomes in the time span of the program," Schuh added "So there are [multiple] deliverables: obviously potentially speeding up the diagnosis by using cell-free technology [but also] training the future generation of clinicians and scientists in genetic and genomic technologies in sub-Saharan Africa."

Earlier this month, Schuh and colleagues began a first stage of local pathology training. "We have brought in a mobile slide scanner... so proper telepathology can happen and pathologists can get second opinions to speed up the diagnosis … trying to get the pathology to the highest level it can be," she said.

Importantly, according to Schuh, all the sequencing in the program will be done onsite. Illumina has donated two iSeq instruments for the project, which are already installed at the Muhumbili University of Health and Allied Sciences in Tanzania.

"Not a single sample will leave the country, so that will force everybody to create capacity, and that's not just capacity of sequencing [and] training some very bright and enthusiastic people," she said. "It also means that the companies, whether it's drug companies, whether it's biotech companies, will need to be able to ship reagents, which is actually at the moment the [main] obstacle we have."

Finally, Schuh said, the investigators have made it a point to ensure that the program will give kids access to best current standard of care therapies, which means about a third of the overall budget is going to procuring the monoclonal antibody therapy rituximab, which is increasingly used in combination with chemotherapy, at least in the west.

"The biosimilars [for this drug] are now FDA-approved in Tanzania and Uganda, and we want to make sure that the kids get the same treatment that they would get in developed countries," Schuh said.

Dennis Lo, who pioneered the methods for blood-based viral-cancer detection that have been the backbone for what Schuh and colleague will be deploying, said in an email that he's corresponded with the Oxford team and, based on his ongoing research analyzing a variety of EBV-associated cancers, he's confident that their assay approach should work well.

For early detection and screening, which is what Lo has been pursuing for EBV nasopharyngeal cancers, an important part of assay validation has been making sure that the circulating viral DNA detection method is not just sensitive, but also highly specific, so that it doesn't pick up false-positive cases of non-cancer EBV infection, or virus reactivation.

Schuh said that this is not an issue for the team's goals in Tanzania, because the aim is not to screen for cancer, but rather to make a diagnosis that is already suspected faster and easier.

That said, she added, there could potentially be a case made in the future for a screening program for these children. "You could argue [that might be an] economically viable thing to do, especially in the areas in the region around Lake Victoria where this is really very common," she said, adding that this would have to be studied further.

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