liquid biopsies

The area of early cancer detection continues to become ever more exciting these days. Each month more companies add liquid biopsies to their product offering as new technologies advance and are able to recognize cancer with increased sensitivity and specificity, particularly from cell-free DNA in the blood.

Last year we talked with one of these companies, Biological Dynamics, which had a technology based on electrical detection that excels at characterizing exosomes. The company is now led by a long-time friend of the program, Dr. Paul Billings, and our guest today. Coming off a stint as the Chief Medical Officer of Natera, an emerging leader in cell-free DNA cancer testing, Paul says he’s had an advisory role with Biological Dynamics and at one point served as their chairman before now taking on the role of CEO. His leadership coincides with the publication of a paper in Nature showing some "very excellent performance" of the company’s technology at detecting pancreatic, ovarian, and bladder cancers in patients.

Paul shows great enthusiasm for the exosome which, he says, comes from the fact that exosomes have more potential than ctDNA for detecting early-stage cancers. Why? For one, he says, the exosome is more stable. And Biological Dynamics’ platform is particularly well suited for looking at exosomes.

Paul has a more focused strategy for the early cancer detection market. When early detection technology first came on the scene, we heard a lot about “pan-cancer screens.” But while the company is working on a general screen, Paul says that they plan to begin by launching a follow-up testing service for those who are already at high risk for cancer.

“Providers of germline tests really need the support of accurate early detection for those people who are found to be at risk. And we want to be providing tools for those families who are at high risk and improving the experience of the risk and managing the risk."

Alec Ford is passionate about his message. No wonder. There's an astounding fact in cancer medicine that is little known and could make a big difference. More cancer patients are dying from infections than they are from their cancers. And Alec's company has the technology to do something about it.

“We celebrate every new therapeutic advance. We celebrate every new diagnostic advance--and we should--every new advance for cancer. And yet the very number one thing that will take the lives of cancer patients in America in 2022 is infection. And quite frankly the world is pretty quiet about what we can do to move the needle. And yet it is the biggest needle there is," says Alec in today's show.

Alec is CEO of Karius, a company that can detect infections in the blood through a DNA-based liquid biopsy test. We featured the company four years ago when they had come out of stealth mode. Alec says today the company has a proven track record with clinical and analytical validation to back up the testing. They recently became the first metagenomic cell-free DNA testing company to be accredited by New York State. And the company has zeroed in on immunocompromised patients, particularly cancer patients as those they can help the most.

Raj Krishnan has a good story, and probably a good product. More data will tell. He's the CEO of Biological Dynamics, a new liquid biopsy company that is able to detect biomarkers in not only blood but other biological fluids. And the company's products are good for not only cancer but Alzheimer's and other disease areas as well.

Raj comes to precision medicine from electrical engineering. You don't hear that very often. One day in his lab while working on his PhD he had a classic eureka! moment. That unexpected discovery for which every scientist longs.

"The vast majority of methods for isolating biomarkers are either chemical or mechanical. Very few are electrical. And as an electrical engineer, I stumbled upon this methodology. At the time I was originally working on this, it was thought to be theoretically impossible. Late one night I came upon the answer."

The important thing about Biological Dynamics' technology, called ACE, is that it is able to draw the biomarker out of the sample without disturbing the biology. It is able to leave it in what Raj refers to as the "native state."

"Take a look at any Qiagen kit workflow or magnetic bead workflow and you can see 400 steps of which you have: destroy this, capture this, run this. How do you know fragmentation isn't being done by what you're doing to isolate the biomarker, as opposed to what it was in its native state?"

We have spatial biology. Should we call this native state biology?

When we talk precision medicine on Mendelspod, we’re usually talking about oncology. But today we shift our focus to diabetes.

Raghu Mirmira is an MD PhD at Indiana University who is working on a panel of biomarkers that would predict Type 1 diabetes. That’s right. Predict.

Having already found a DNA biomarker candidate which detects dying beta cells using the new technology of digital PCR, Raghu is now working to improve the panel with other metabolites.

Will we some day have a Myriad Genetics for diabetes? Raghu says, yes. But he warns that we must also develop new treatment options to go along with a predictive blood test.

“Before we get to the point where this is a commercially available test, we need to be doing further studies to figure out what’s the outcome of individuals who test in a particular way. And what kind of interventions could improve those outcomes in some way.”

The history of science is also a history of toolmaking. And nowhere is this more true than in modern biology. New instruments in the lab allow biologists additional modes of discovery, new levels of quantification, and the opportunity to pursue new and old questions with more data.

David Polsky is a dermatologist and researcher at NYU’s Langone Medical Center. Last week he received a grant from the NCI for readying a new liquid biopsy test that tracks the progression of melanoma for the clinic. Until now, there has been no blood based marker that was able to track melanoma as there is with other cancers such as prostate cancer and the PSA (prostate specific antigen) score. This new test, which could be a major breakthrough for the treatment of melanoma, targets seven mutations which occur in 70% of melanoma patients. These mutations are found in cell free, circulating tumor DNA.

In today’s interview, David points out that the test is possible only with the advent of digital PCR and its ability to measure DNA more with absolute quantification and sensitivity. We knew these mutations before, but just couldn't measure them.

“Droplet digital PCR has been a major breakthrough in our ability to detect rare events and also to quantitate them with accuracy and precision. Those two features are absolutely critical,” says David.

David and his group have been collaborating on the test with Bio-Rad, who makes the ddPCR instruments and designed these tests, and with Molecular MD. Clinical trials with Bristol-Meyers Squibb are expected. Now, with the preliminary science published, the NCI grant will go towards developing analytical and clinical validation so that the test might be commercially available for patients soon.

There’s been lots in the news this past year about liquid biopsies—those non-invasive tests which locate biomarkers in a vial of blood. Much of that press (perhaps too much) has been about using these blood tests for cancer screening: predictive tests that could be available to consumers some time in the future.

But according to today’s guest, the real news about liquid biopsies is that they are in use now. Michael Nall is the CEO of Biocept, a company based in San Diego which has gone about as far as any organization in commercializing these non-invasive tests. They offer tests for many kinds of cancer, including breast, colon, prostate, and lung.

“The area we’re focused on really hasn’t gotten as much attention [as the cancer screening tests]. And yet it’s the nearest term and the biggest unmet medical need today: how do you help patients who have been diagnosed with cancer and who are progressing?” says Michael in today’s interview.

Biocept stands out in the space for not only their comprehensive line of testing, but for their demonstration of just how to commercialize these tests. The company has thirteen salespeople around the country who call directly on clinics. They are focused on two niches: cases where the cancer has metastasized in the bones or the brain and cases where not enough or no solid biopsy can be obtained.

Most importantly, Biocept has succeeded in getting paid for their tests using the same existing CPT codes that are used for the solid tumor tests.

Will we soon see a time when the liquid biopsy is the preferred test? How is Biocept preparing for impending FDA regulation? Hear this early success story for a pioneer in a rapidly growing field.

It’s the beginning of the age of liquid biopsies, when less invasive, regular blood draws will provide more information than the occasional solid tissue biopsy. Companies that offer tests based on circulating tumor cells or cell free DNA in the blood are popping up like genome interpretation companies were a few years ago. As our understanding of biology at the molecular level advances--particularly in the field of cancer research--the more this practical and focused approach for teasing out the information in the cell, in the body gains steady adoption.

The success of prenatal diagnostics with a small amount of blood from the mother has shown us—and investors—that there’s there’s a wealth of information and money to be made from blood samples. And the promise of a non-invasive procedure to provide more important data than traditional biopsies can seems too good to be true.

Yet, we’re still in the early days. Few liquid biopsy tests have been commercialized. Today’s guest, Murali Prahalad, is the CEO of Epic Sciences. They are touting a new platform for analyzing circulating tumor cells, or CTCs. This has been a tricky space for companies (remember On-Q-ity?), so the big question for Murali is what makes Epic better?

Murals says that previous CTC technologies made some "grounding assumptions," such as that the cells had to have surface proteins used to isolate them, or that they had to be larger in size than the surrounding white blood cells.

“What we’ve said is let’s admit we don’t know what we don’t know. So let’s shotgun this. Let’s look at all the nucleated cells and get them on a proprietary glass slide and then use a mixture of staining, imaging, and computation techniques to really figure out what’s cancer from normal. So we’re not making any grounding assumptions here. And what it’s done is reveal a far greater range of these species in the blood than we ever thought possible. . . . We let the biology reveal what we should be worrying about.”

That all sounds fair and good. Now how will Epic take their latest studies and commercialize them into clinical assays that doctors can use?

For inspiration, Murali draws on the history of HIV drug development. It is now customary for AIDS patients to keep regular counts on their viral load as they manage their illness with one pill a day. This type of regular screening using just blood samples could become the norm in cancer as well. Quoting Mark Twain, Murali says, “history may not repeat itself, but it does rhyme."

As we begin the countdown to the new year, we take a look back at 2015 in cancer research, treatment and prevention. Mendelspod is increasingly becoming known for the coverage of genomics and precision medicine, and cancer as a disease area offers a specific window whereby we can look at practical outcomes.

Anna Barker is the director of the National Biomarker Development Alliance (NBDA). Formerly the deputy director of the National Cancer Institute (NCI), she has worked on cancer her entire career and seen first hand the triumphs and setbacks. Last month at the National Press Club in Washington, D.C., Anna announced the creation of GBM-AGILE, a new kind of clinical trial for a very tough, rare cancer, glioblastoma multiforme. The project is the culmination of the work of Anna and many others to come up with a better system for validating biomarkers. This single trial is a global endeavor and already becoming a "movement" in cancer research with over a hundred and forty experts getting involved. Folks at the FDA are saying that GBM AGILE “raises the bar for clinical trials.”

Along with new ways of doing clinical trials, 2015 has also seen the explosion of new blood-based cancer tests known as liquid biopsies. Still mostly research projects, these tests will potentially offer patients a non-invasive alternative to expensive and painful solid tumor biopsies and offer the promise of someday improving cancer screening and prevention.

Immunotherapy drugs continued to dominate the list of FDA cancer drug approvals in 2015 with the first approval of an oncolytic virus therapy and the first approval of combination immunotherapy. In today’s interview, Anna reminds us that the recent breakthroughs in immunotherapy are the result of a 40 year journey. She goes on to question the herd mentality reflected in the over pursuit of certain targets.

Anna wraps up her review by pointing out the opportunity to go after rare cancers, such as GBM and some childhood cancers. She says the more common cancers such as the big epithelial cancers—breast and lung— are dauntingly complex with "gazillions of mutations.” But with rare cancers, “we can follow the genomic changes through to the cells, to the organs, and to the organism. I’m thinking that we should all begin to take a careful look at some of the rare cancers,” she concludes.

We set up an interview with David Spetzler, the CSO of Caris Life Sciences, to hear about some promising new liquid biopsy tests they are developing. And we do that in today’s show. But first, the interview takes a turn toward the regulation of molecular tests. Spetzler says that Caris is already doing as many quality certifications as possible short of FDA oversight.

“We are actually quite favorable to increases in regulation,” he says, “We think there’s a lot of bad science being done, quite honestly, because it’s expensive to take the additional steps to insure that high quality work is being performed. And we’re doing those steps, so we might as well get credit for it.”

At the same time, Spetzler says that an appropriate framework to evaluate the utility of molecular profiling is missing. Traditional blind trials don’t work for molecular tests, he warns. The studies must be more longitudinal and be focused on more than just one biomarker at a time. Caris is currently running a study that “backs away from individual biomarker validation and focuses on process validation to identify underlying treatment opportunities for patients with particular molecular profiles.”

We do get to a discussion of Caris’ upcoming liquid biopsy tests, such as one that screens for breast cancer. This past year we’ve seen an explosion in the industry of these new non-invasive, blood-based tests. But whereas most companies are looking at cell free DNA (cfDNA) or circulating tumor cells (CTCs), Caris has come up with a novel platform using exosomes. These are small vesicles that handle intracellular communication and are not only present in all biological fluids but much more ubiquitous than cfDNA or CTCs.

Cliff Reid, CEO of Complete Genomics, is back on the conference circuit, touting a new product. After years of building his company to do sequencing as a service, Cliff presented data at last week's ASHG meeting on Complete's first sequencer as a product, or what they are calling the Revolocity supersequencer.

Cliff was a pioneer in developing the service model, offering only whole human genome sequencing. But after being bought out by BGI, who already had a service business in China, he was compelled to shift his business model to that of selling sequencers.

So where does this position Complete in an already crowded and mature sequencing tools market? And how does Cliff see the future of clinical sequencing? Cliff says that the new Revolocity offers the highest quality of any of the other sequencers. This is an impressive claim in a world where PacBio customers are saying they can get up to 100% accuracy with deep enough sequencing. As for throughput, the new supersequencer is similar to Illumina’s HiSeq X Ten system, producing about 10,000 whole human genomes per year.

However, Cliff says that high quality and high throughput are not the important part of the story here. “That's historically what people expected from us,” he says in today’s interview. "The most important thing we did with the Revolocity system is that we packaged it for clinical researchers and clinical use. The packaging is end-to-end.”

Strangely, in an age when longer sequencing reads have enabled genomic research to go to further heights, such as with HLA typing, the new Revolocity does not incorporate Complete’s LFR or Long Fragment Read technology. Long read sequencing is still a highly specialized effort, Cliff argues. Rather, he says, “we haven’t used the technology that we have today [short read technology]. What we need to do is sequence a million genomes."