With enough sensitivity to detect and trap a single at-large cancer cell from among a billion blood cells, the impressive new Circulating Tumor Cell (CTC) microchip is showing much promise as it points the way to a new era in the fight against cancer. Proudly ushering the microchip from its technological cradle to where it will fill an all-too-long vacant seat at the clinical table is a multidisciplinary research team headed by NIBIB Quantum Grantees, Drs. Mehmet Toner, Ph.D., of the Massachusetts General Hospital (MGH) BioMEMS (Biomicroelectromechanical Systems—also called P41) Resource Center, and Daniel Haber, M.D., Ph.D., of the MGH Cancer Center.

A Very Nice Surprise

In the world of nanotechnology, where the classical laws of physics don’t always apply, the answers are hardly intuitive. That said, Toner reports that the CTC microchip was, “…a very nice surprise. Very early on, the idea was to use this technology with microposts coated with antibodies to fractionate blood into its common cellular [immune] components. But it turned out that the microfluidic technology we developed had very high sensitivity for isolating cells from whole blood. From that perspective, it really surpassed our expectations.”

Taking the “Ouch” Out of Medicine

When it comes to cost, convenience, and comfort, compared to other clinical tools, the CTC microchip will be a real gift for cancer patients. Toner estimates that, once the chip is in full production, manufacturing cost will shrink to around $50 to $100 per microchip. He adds, “From a cost comparison standpoint, the chip analysis will certainly be much lower than the cost of a PET or CT scan, and patients won’t have exposure to the radiation of these other tools. Also, scans have to be done in a high-end imaging center, which may not be anywhere near the patient’s home. This microchip analysis will eventually be done right in the doctor’s office.”

As for additional costs, pain-wise, cost is the prick of a needle to retrieve a common 10 milliliter blood draw. This sample size contains about 80 billion cells from which the chip can pinpoint and capture anywhere from 50 to 500 cancer cells. Other cancer biopsies can be highly invasive, and perhaps surprisingly, are only done once.

Toner uses prostate cancer as an example to explain current biopsy concepts, “Typically, a biopsy is done at the time of diagnosis. Then 20 years may pass before the prostate cancer relapses, but the biopsy done 20 years ago is the one that is most likely to be used clinically to make judgments on treatment. The problem with that approach is that cancer is a living disease. It can alter itself, and 20 years later, the biopsy might not accurately reflect the tumor’s genomic status, and may not reflect the state of the cancer at the time of active disease. So being able to capture cells that have broken away from the primary tumor while they are traveling in the bloodstream offers real-time or current access to the tumor without subjecting the patient to another more invasive biopsy. The quality of information is superior, and adding in the minimally invasive nature of our test, we have a very attractive clinical tool."

The Blood Biopsy: Getting Personal

Because most cells remain alive through CTC microchip processing, it also offers the possibility of monitoring the patient for more selective, personal parameters. From a treatment standpoint, this can be critical, because further analysis of factors, such as genetic status of the cancer, can provide data that enables doctors to prescribe more precisely targeted therapies.

Toner explains his group’s unique research perspective and how it translates into more personalized medicine, “Our center's mission is really to explore technologies for the living cell. Many have used these technologies at the molecular level, but very few have explored the applications in cellular systems. Monitoring, early detection of relapse, and management of each patient on their own merit is very important, and more and more genetically based drugs are becoming available.”

“For example, lung cancer patients representing only about 10 to 20 percent of the population have mutations in the EGFR gene, and this population is known to respond very well to drugs known as tyrosine kinase inhibitors. Solid tumors are not easy to feel, and you can biopsy some of them, but not most. So the ability to have a “blood biopsy,” so to speak, where you can look at the genetic makeup of the tumor, is key. With this information, the doctor can treat the patients using targeted drugs in a more timely fashion, and more effectively.”

Filling the Gaps

Toner provides interesting perspective on the looming enigma of present-day clinical diagnostics and makes a case for various applications of his CTC microchip. He says, “The fact is, there are thousands of things in our blood that could tell us pretty much everything that is going on in our body. There are dendritic cells that tell us about the immune system; during pregnancy, fetal cells get into the maternal circulation that could tell us about the health of the fetus; in cancer, circulating tumor cells can tell us many things about the patient and the disease…”

Pointing out a rather glaring technology gap in clinical medicine that the average person isn’t likely to notice, Toner adds, “Think about it. Right now, there is blood testing, and from there, we jump immediately to high-end imaging modalities—there is nothing in between. Today’s blood tests, which are currently the most prescribed type of test in clinical medicine, can count the number of cells, look at electrolytes and glucose, and do so many other things. But even with all the information revealed by these analyses, the tests are extremely insensitive, and not very specific, because the information could indicate any one of several different disease states.”

“Very commonly, as the needs of biological science become more sophisticated and complex, we continue to try to accommodate those needs with available technology, but that doesn't always work. [Other similar existing technologies] can only process tiny amounts of blood that wouldn’t be sufficient for cancer detection, or if they can process larger volumes, they have major losses in the process of handling blood and the viability of the cells is compromised.”

Highlighting various potential applications for infectious and systemic disease, such as tuberculosis, heart disease, vasculitis, and stroke, Toner reports the chip has become very popular, but is still not developed to the point where it can be generally available.

Collaboration, Collaboration, Collaboration

With today’s most challenging technological dreams being nurtured in a multidisciplinary research environment, a new kind of collaboration has become an essential component in the Quantum Grant strategy. Not so unlike the Vulcan mind meld, Toner describes the kind of teamwork that has become standard practice in his laboratory, “Getting technology to people’s bedside is not an easy thing to do because the research problems we are working on today are more and more complex. You need to integrate well with collaborators, on a day-to-day basis, so that they can help you think about problems and issues in areas where you’re not an expert. You have to create an environment where you actually think together—morph together—sharing information, access, and also sharing credit."

Toner, who has been working in multidisciplinary environments since the beginning of his academic life, says one must first recognize the disciplinary boundaries, keeping in mind that crossing the lines will require an ability to think in completely different ways about research problems. "The Quantum Grants take a major medical problem where engineering could have a great impact, and they put together a multidisciplinary team to tackle the problem. It requires people who are working closely together, and requires us to take on a bigger challenge than we would ordinarily. A lot of people still don’t realize the importance of thinking together with someone else about research—it’s critical. It might be easy to think you could just go to a collaborator, get some ideas, then go back to the lab and finish the work, but it just doesn’t work that way if you’re serious about work on a really high-impact project.”

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It’s Just a Phase: Cool Technology

The “one-two punch” of CTC microchip research success has thus far been realized through the tandem impact of QG funds and the NIBIB-funded BioMEMS Resource Center, which, in Toner’s words, “…has been a unique environment, nurturing the translation [of the microchip] from a ‘cool technology’ phase, to a ‘real technology’ phase with great potential for impact at the patient’s bedside.”

“The P41 structure is very clever. The BioMEMS experience has impacted my own research group to become more translational, and we do it better than we could in the past. Work at this scale showed me how much more impact one can have—not just publishing scientific papers, but having a real impact. You have to step forward into full-scale collaboration to make significant strides forward translationally.”

Toner compares the BioMEMS research structure to the layers of an onion. At the core of it all is the P41 mission, which is to develop cutting-edge, enabling technologies that will have a significant impact in biomedical sciences. The next layer is collaboration with other biomedical scientists who will benefit from new technologies.

The third P41 layer is ‘service,’ which is different than collaboration. Toner explains, “When you get to the service component, you know you really have something your research peers want. A number of groups might want to use the technology, but we sometimes just provide the chip without a lot of interaction.”

The final two BioMEMS layers are training and dissemination. He says, “In addition to developing cool technologies, we need to put it in the hands of collaborators and service users, and we need to educate the potential end users. This stratified process has been a very effective strategic approach for technology development—not just for cancer, but a number of other projects.”

Toner appreciates the wisdom behind NIBIB’s requirements for the Resource Center. “In order to get continued funding, we have to be able to disseminate the technology. This is extremely critical to development, because by working together with end users, we can really sharpen the functionalities and specifications of the technology.”

It’s About Time

With data from hundreds of subjects—primarily lung cancer patients, but also prostate, breast, and colon cancers—it is still too early to speculate about the microchip’s actual contributions to patient survival. Toner says, “That will be part of the next phase of our Quantum Grant, which will have a longer trial, and human validation trials, to show that this technology could have a real impact.”

Toner echoes the early diagnosis mantra, emphasizing this as the one critical factor in beating any kind of cancer. Statistics strongly support his view. Regarding cancers of the lungs and bronchii, the National Cancer Institute (NCI) 2006 SEER Stat Fact Sheet contains sobering information on the inverse relationship between cancer status at time of diagnosis and 5-year survival rates: The 15% of lung/bronchus cancer cases diagnosed while localized specifically at the site of its genesis have a 52.6% likelihood of survival 5 years following diagnosis; 22% are not diagnosed until the cancer has spread to nearby lymph nodes and tissues close to the primary site, and this group has a 23.7% chance; and 5-year survival rates for the 55% diagnosed after the cancer starts to spread is only 3.5%.

Clarifying the statistical message, Toner says, “Generally speaking, very early cancer is when the tumor is growing in only one location, and it’s still only about a half a millimeter in size. After that, because tumor cells have a higher metabolism and need more oxygen and nutrients than normal cells, blood vessels start building around them. At this point, the tumor can metastasize, which means it starts putting its cells into the bloodstream, and that’s when they start traveling to other parts of the body, giving the cancer much greater potential to spread.”

The various cancers naturally progress at different rates, and the stealthy nature of the disease has tremendous impact on ultimate health outcomes because symptoms may not manifest themselves until a tumor is significantly developed. Thus, the ultimate cancer weapon of the future will be a diagnostic tool—perhaps used at the time of a yearly physical examination—that can detect the disease before vascularization occurs, and certainly, well before onset of symptoms. 

Toner says, “Ovarian and pancreatic cancers are silent diseases. You don't know it’s there until it’s in advanced stage. But even with all the tools for diagnosis we have for things like breast cancer, too many people don’t go to their physician until their lymph nodes are affected. Even at that stage, the symptoms might go silent and a patient might subsequently defer that doctor’s visit. In the case of prostate cancer, it can take 20 years for the disease to become active, but in the pancreas, it could be only a few weeks."

"Early detection is going to have the biggest impact, and this CTC technology has potential for that. When we realized the chip’s potential for sensitivity, we started to put more emphasis on rare cell detection, but as for using it to screen patients for early detection, the technology is not ready for that yet. We are working on higher sensitivity chips using different post geometries and different flow conditions to find out what has merit.”

A Chip Off the Old Block: Future Generations of CTC Technology

Driving forward at warp speed, Toner and his team already have big plans for the fledgling technology. With the voice of a proud parent, his enthusiasm is audible as he tells about the CTC chip of the future. “Just like the laser, which adapted to so many applications with different power and different ways to manipulate light, this microchip will probably have many iterations, and its capabilities will definitely evolve. Our most important task will be to find rare cells, which is critically important to current-day clinical medicine.”

AIDS brings a whole new set of challenges to the lab bench, but also new possibilities. Other applications to be explored in the next 3 to 5 years include testing the chip for its ability to monitor AIDS patients’ therapy, or track patient status for other bacterial infectious diseases.

“We have a hand-held device and an AIDS chip that monitors CD4 antigens on T-lymphocytes that tell whether AIDS is in active form—that is also a P41 Resource Center-originated technology that we’ve tested on patients at Mass General Hospital. Now it's being scaled up for use in Africa as a Point of Care (POC) device. The challenge here is to build a chip that can be used in limited-resource environments in Africa. It's a technology that needs to be very simple, very portable, and the cost must be just pennies, and that's a whole different engineering and technical ball game.”

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