NEWS & EVENTS
This is a production of the National Institute of Biomedical Imaging and Bioengineering, part of the National Institutes of Health
Host: Margot Kern
Toner: The benefits of finding circulating tumor cells is multifold. It could really turn cancer into a manageable disease.
Kern: You’re listening to Mehmet Toner, a professor of biomedical engineering at Harvard University, who led the development of a microfluidic device that can isolate circulating tumor cells from whole blood samples.
Kern: Circulating tumor cells, also known as CTCs, are cells that have broken off a solid tumor and entered the blood stream. While most CTCs die in the blood, a small percentage can become embedded into tissues of distant organs where they can begin to form a new tumor. This is how cancer spreads or metastasizes.
Kern: But, despite their ill-effects, these cells have a silver lining. The presence of CTCs in the blood can actually help doctors monitor whether a particular treatment is working.
Toner: If the circulating tumor cell number goes up or down as the patients are on treatment, you would know very quickly from the blood test.
Kern: In addition to monitoring CTC number in the blood, the DNA of circulating tumor cells can be analyzed to look for cancer-causing mutations, information that can be used by doctors to determine what medications may be most effective.
Toner: Most drugs now, almost exclusively, all new drugs are based on targeted therapy where patients with specific mutations respond to specific treatments, targeted treatments, that are less toxic, much more effective.
Kern: The advantage of analyzing CTC DNA is that information about a specific tumor can be procured from the blood, thus, negating the need for a tissue biopsy, a procedure that can be extremely painful for some patients and difficult to carry out.
Toner: So you’re doing a liquid biopsy, in a sense. You find these cells in blood and then look at their genomic makeup and decide what drug they should be put on.
Kern: Sounds simple enough. Well, it would be if it weren’t for the fact that circulating tumor cells are nearly impossible to catch.
Toner: They are one in a billion, one in 10 billion, so it’s really looking for a needle in a haystack, if not worse.
Kern: To give you an idea of the size of this haystack, for every milliliter of blood, there are a few million white blood cells, around a billion red blood cells, and only between 1 and 10 circulating tumor cells. Those are pretty tough odds, but it turns out they’re not insurmountable.
Kern: Over the past several years, Toner has worked to develop a microfluidic chip that can separate the rare and valuable CTCs from the billions of other cells found in a patient’s blood.
Toner: The way we find these cells is when you go to a physician’s office, you give a tube of blood, that tube of blood goes through the chip. The chip has very precise flow conditions and this way we can very precisely and rapidly isolate those rare cells.
Kern: The CTC chip technology was initially developed with support from an NIBIB Quantum grant. They’re called quantum grants because the goal is to achieve a profound or quantum leap in healthcare. Toner says they’re making that leap:
Toner: We are developing a new technology that didn’t exist before. We are trying to understand the biology of these cells, because we know very little about these cells, and we are trying to identify and clinically validate applications, and that’s a pretty tall order, and it cannot be addressed by standard grant mechanisms. Quantum grants was the exact structure we were looking for.
Kern: Toner says the interdisciplinary nature of the project has been integral to its success, but also one of the most challenging aspects.
Toner: Our team has engineers, biologists and geneticists, and clinicians. The ability to pull a team like that together, getting everybody motivated, create the right incentives, and solve complex problems is really very difficult. I think that was the most difficult part, and it’s the part that requires a lot of attention, I call it social engineering. That’s the part that really fuels the entire enterprise
Kern: The beauty of the CTC chip says Toner is it wouldn’t place any additional burdens on the patient or physician.
Toner: It’s really taking the blood. We do that every day for millions of people. And instead of looking for X, Y, Z, now you’ll be looking for circulating tumor cells using this technology. So it really fits into the flow of physician-patient interaction very easily.
Kern: While not yet available clinically, nor a complete substitute for current cancer care, technology like Toner’s microfluidic CTC chip could someday make monitoring and treating cancer more manageable for clinicians and patients alike.
Toner: It will enable, in the long run, to treat the right patient with the right drug at right dose at the right time.
Kern: For NIBIB, I’m Margot Kern
This is a production of the National Institute of Biomedical Imaging and Bioengineering, part of the National Institutes of Health.
Host: Margot Kern
Kern: Venous ulcers affect approximately 1% of the population. These chronic wounds occur when valves in the veins of the leg malfunction, and they can take months and occasionally years to heal.
Kern: Dr. Michael Weingarten, Chief of Drexel University’s vascular surgery department and a specialist in chronic wound management, says venous ulcers are a significant economic burden.
Weingarten: To put it in perspective, it’s a chronic problem accounting for probably several billion dollars in healthcare costs in the United States, and it’s prevalent not only in elderly patients but also in working age patients. So, we’re talking about expenses in terms of treating the wounds, but also time loss from work, disabilities, things like that.
Kern: Currently, the standard treatment for venous ulcers involves controlling swelling, taking care of the wound by keeping it moist and preventing infection, and a technique called compression therapy in which patients wear special socks that squeeze the leg to prevent blood from flowing backwards. But Dr. Weingarten says these measures are lacking.
Weingarten: These are what we call passive treatment modalities. We try to change the homeostasis of the wound so it’s ideal for healing and that can be very difficult. There are very few active technologies that actively stimulate healing for these ulcers, in particular.
Kern: But that may soon change. With support from NIBIB, a research team led by Dr. Peter A. Lewin, a professor of biomedical engineering at Drexel University, has recently created a novel battery operated ultrasound patch that can accelerate healing by delivering low-frequency, low-intensity ultrasound directly to wounds.
Kern: In a recent pilot clinical trial of twenty patients, the team reported that patients who received therapeutic ultrasound treatment using their patch, in addition to standard compression therapy, had a net reduction in wound size after just four weeks. In contrast, patients who received only compression therapy had an average increase in wound size at 4 weeks. Surprisingly, the greatest effect was seen in a subgroup of five patients who received the ultrasound treatment for the least amount of time (just 15 minutes per week) at the lowest frequency (20khZ). All five patients in this group experienced complete healing by the fourth week.
Kern: Dr. Weingarten was impressed by the results:
Weingarten: This is a very difficult population to heal in a timely manner, and so, yes, it was rather surprising.
Kern: While using ultrasound to accelerate wound healing is not a new idea, until now, it’s been difficult to prove its clinical efficacy. One reason is that studies have used a range of ultrasound frequencies, and it turns out that lower frequencies may be better at promoting healing. So says Peter Lewin.
Lewin: We had an idea that if some of the mechanisms which were proposed by us in the literature would work, they probably would be better or more profound if we applied them at the lower frequency. Typically the therapeutic ultrasound is applied at 1-3 megahertz, we went down to between approximately 20 and a 100 kilohertz. So it’s at least a magnitude of order lower.
Kern: The team’s clinical findings were supported by experiments conducted in the lab in which cells involved in wound healing were treated with low-frequency ultrasound. The team found that 15 minutes of 20khz stimulation caused both an increase in cell proliferation and cell metabolism just 24 hours after receiving the treatment.
Kern: According to the team, one of the most challenging but also important components of the research was developing the battery operated ultrasound patch. Lewin says the device offers tremendous value to patients because it gives them the option of receiving frequent treatments without having to return to the clinic, ultimately increasing patient compliance, while saving money.
Lewin: So the whole device is approximately a 100 grams and it’s connected to the fully wearable two batteries, which are fully rechargeable, so the patient can have the device on the wound, if needed, twenty four hours a day.
Kern: The team is now working to develop an additional component of their patch which would allow physicians to view subtle tissue changes during and directly after ultrasound treatment using near infrared spectroscopy.
Kern: Lewin says the ability to monitor changes in the wound tissue during treatment would allow physicians to optimize the frequency, intensity, and rate of the ultrasound delivery for each patient. Going forward, the team plans to test their patch on a larger group of patients and to expand their studies in the lab, examining different types of cells involved in wound healing.
Kern: Josh Samuels, a Ph.D. student in Lewin’s lab says some of these mechanistic studies are already under way.
Samuels: We’re looking now a lot more at the macrophages and we’re also looking at fibroblasts. We’re trying to look at the different levels of wound healing. We know there is the inflammation phase, the proliferation phase, and the remodeling and we’re looking at the primary participants at each phase. So we know the endothelial cells are going to play a big role and the macrophages. So we’re actually examining the effects of ultrasound on each individually and then we’re going to look collectively to see if there’s cascade effects, see if one influences the other. That’s really where we’re at now with our in vitro studies.
Kern: For NIBIB, I’m Margot Kern.
Researchers help nanoparticles carrying tumor-fighting drugs evade the immune system
This is a production of the National Institute of Biomedical Imaging and Bioengineering, part of the National Institutes of Health.
Welcome to the NIBIB science highlights podcast. Nanoparticles are being used by researchers and most recently in clinical trials to ferry cancer-fighting drugs to tumors. The use of nanoparticles as a drug delivery mechanism could allow doctors to give patients higher doses of toxic medications while sparing healthy tissue. But the immune system poses a major obstacle to nanoparticle delivery. That’s because nanoparticles are viewed by immune cells as foreign bodies that should be eliminated.
I recently spoke with an NIBIB grantee, Dr. Dennis Discher, a molecular and cell biophysicist in Chemical and Biomolecular Engineering at the University of Pennsylvania. Discher published a paper in Science on Feberury 22, 2013 in which he describes a new method developed by his lab that helps nanoparticles escape attacks from cells of the immune system, specifically macrophages.
Dr. Discher, for those of us who aren’t familiar with the biology of the immune system, what is a macrophage?
A macrophage is a giant (macro), phage or (phagos); it means eating in Greek. So it’s a giant eater. And, they’ll eat nanoparticles, they’ll eat microparticles, microbes, but even in implants, if you implant a giant object that’s much bigger than the size of the cell, these cells will try to eat it and in frustration they’ll start fusing and forming a giant multi-nucleated cell, a true giant macrophage. So often with particles in modern times or implants, we really don’t want this innate immune system to attack what it’s had eons to evolve its expertise to do.
In the Science paper you attached a protein called CD47 to particles and this prevented them from being recognized by macrophages as foreign. How was your attention first called to this particular protein?
So we, like many other people, in fact I would say most people, as we injected particles into the bloodstream in studies more than ten years ago, we’d find that too many of our particles were taken up by macrophages. And then a paper appeared in Science about thirteen years ago from a group in St. Louis that reported a mouse that has a specific protein on the surface of really all the cells. It’s a protein called CD47. They described it as a marker of self as passivating macrophages, as a protein that normally, on normal cells, limits macrophages from eating the cells, and when they knocked it out in a mouse, well they see macrophages in other mice eating cells taken from the mice that had the CD47 protein missing.
So then, what did your lab do with this new information regarding CD47?
There were clearly questions that arose. This was obviously a study in a knockout mouse that left us scratching our heads. And we really wanted to know, would this work on humans and would it work on our particles and maybe other types of materials. I mean macrophage interactions not only with particles but with everything we implant in the body.
So then how did your lab determine if human CD47 has the same function as mouse CD47?
We aimed to understand human CD47 on human cells starting with human blood cells because mouse blood cells is where this other paper from the St. Louis group had started. And we worked up to understanding the integration and the differences with mouse and then expressing the protein and showing that we could put human protein on a plastic microparticle and inhibit phagocytosis in a dish.
How then did your lab bring this to studies in animals?
About the same time that our paper appeared, a group in Toronto published that there was one strain of mouse and this NOD/SCID strain of mouse, human CD47 interacts with macrophages of that strain of mouse and no other strains of mice. The receptor is called SIRPα. (It doesn’t really matter.) But, you now have a mouse receptor compatible with human CD47 that prompted us together with additional information to really take this in vivo.
In the Science paper, you inject these NOD/SCID mice with nanoparticles that have human CD47 attached to them. But you don’t attach the full CD47 protein. Why?
Human CD47 is somewhat different within the population. The receptor, the SIRPα, is certainly different within the human population as it is within different strains of mice. So we studied a crystal structure of the two bonded together and realized that maybe we could minimize CD47 to a universal donor peptide. So we simulated it in a computer, showed that it would doc in silico, and then synthesized it, put it on particles, injected it in this NOD/SCID mouse, and showed ultimately that it was inhibiting uptake of our particles by macrophages.
Discher went on to report in the Science article that he was able to use his CD47-bound nanoparticles to deliver the anti-tumor drug paclitaxel to mice who had been given human-like tumors and that his particles were as good or better at shrinking the mice’s tumors as paclitaxel’s standard carrier, Cremophore, without causing any of the side effects.
For NIBIB News, I’m Margot Kern
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Image of a new vaccine patch that can be self-administered and does not produce biohazardous waste. The microneedles in the patch inject the vaccine into the epidermis layer and then dissolve.