Tumor-Attacking Virus Strikes With ‘One-Two Punch’

Ohio State University cancer researchers have developed a tumor-attacking virus that both kills brain-tumor cells and blocks the growth of new tumor blood vessels.

Their research shows that viruses designed to kill cancer cells — oncolytic viruses — might be more effective against aggressive brain tumors if they also carry a gene for a protein that inhibits blood-vessel growth.

The protein, called vasculostatin, is normally produced in the brain. In this study, an oncolytic virus containing the gene for this protein in some cases eliminated human glioblastoma tumors growing in animals and significantly slowed tumor recurrence in others. Glioblastomas, which characteristically have a high number of blood vessels, are the most common and devastating form of human brain cancer. People diagnosed with these tumors survive less than 15 months on average after diagnosis.

“This is the first study to report the effects of vasculostatin delivery into established tumors, and it supports further development of this novel virus as a possible cancer treatment,” says study leader Balveen Kaur, associate professor of neurological surgery and a researcher with the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. “Our findings suggest that this oncolytic virus is a safe and promising strategy to pursue for the treatment of human brain tumors.

“This study shows the potential of combining an oncolytic virus with a natural blood-vessel growth inhibitor such as vasculostatin. Future studies will reveal the potential for safety and efficacy when used in combination with chemotherapy and radiation therapy,” she says.

The findings were recently published online in the journal Molecular Therapy.

Jayson Hardcastle, a graduate student in Dr. Kaur’s laboratory, injected the cancer-killing virus, called RAMBO (for Rapid Antiangiogenesis Mediated By Oncolytic virus), directly into human glioblastoma tumors growing either under the skin or in the brains of mice.

Of six animals with tumors under the skin, those treated with RAMBO survived an average of 54 days. In addition, three of the RAMBO mice were tumor-free at the end of the experiment. Control animals treated with a similar virus that lacked the vasculostatin gene, on the other hand, survived an average of 26 days and none were tumor-free.

Of the animals with a human glioblastoma in the brain, five were treated with RAMBO and lived an average of 54 days. One animal remained tumor-free for more than 120 days. Control animals, by comparison, lived an average of 26 days with no long-term survivors.

In another experiment, the investigators followed the course of tumor changes in animals with tumors in the brain. After an initial period of tumor shrinkage, the remaining cancer cells began regrowing around day 13 in animals given the virus that lacked the blood-vessel inhibitor. In animals treated with RAMBO, tumor regrowth didn’t begin until about day 39.

“With additional research, this virus could lead to a new therapeutic strategy for combating cancer,” Kaur says.

Story Source:

Adapted from materials provided by Ohio State University Medical Center.

http://www.sciencedaily.com/releases/2009/12/091201102336.htm

Scientists Reveal Malaria Parasites’ Tactics for Outwitting Our Immune Systems

This is an Anopheles gambiae mosquito sucking blood from human skin. This mosquito is the vector for malaria in Africa. (Credit: Wellcome Images)

Malaria parasites are able to disguise themselves to avoid the host’s immune system, according to research funded by the Wellcome Trust and published November 30 in the journal Proceedings of the National Academy of Sciences.

Malaria is one of the world’s biggest killers, responsible for over a million deaths every year, mainly in children and pregnant women in Africa and South-east Asia. It is caused by the malaria parasite, which is injected into the bloodstream from the salivary glands of infected mosquitoes. There are a number of different species of parasite, but the deadliest is the Plasmodium falciparum parasite, which accounts for 90 per cent of deaths from malaria.

The malaria parasite infects healthy red blood cells, where it reproduces. The P. falciparum parasite generates a family of molecules, known as PfEMP1, that are inserted into the surface of the infected red blood cells. The cells become sticky and adhere to the walls of blood vessels in tissues such as the brain. This prevents the cells being flushed through the spleen, where the parasites would be destroyed by the body’s immune system, but also restricts blood supply to vital organs.

Symptoms can differ greatly between young and older children depending on previous exposure to the parasite. In young children, the disease can be extremely serious and potentially fatal if untreated; older children and adults who have grown up in endemic areas are resistant to severe malaria but rarely develop the ability to rid their bodies of the parasite.

Each parasite has ‘recipes’ for around sixty different types of PfEMP1 molecule written into its genes. However, the exact recipes differ from parasite to parasite, so every new infection may carry a set of molecules that the immune system has not previously encountered. This has meant that in the past, researchers have ruled out the molecules as vaccine candidates. However there appear to be at least two main classes of PfEMP1 types within every parasite, suggesting different broad tactical approaches to infecting the host. The most efficient tactic or combination of tactics to use may depend on the host’s immunity.

Now, Dr George Warimwe and colleagues from the Kenya Medical Research Institute (KEMRI)-Wellcome Trust Programme and the Wellcome Trust Sanger Institute, have shown that the parasites adapt their molecules depending on which antibodies it encounters in the host’s immune response. They have also found evidence to suggest that there may be a limit to the number of molecular types that are actually associated with severe disease.

“The malaria parasite is very complex, so our immune system mounts many different responses, some more effective than others and many not effective at all,” explains Dr Peter Bull from the KEMRI-Wellcome Trust Programme and the University of Oxford, who led the research. “We know that our bodies have great difficulty in completely clearing infections, which begs the question: how does the parasite manage to outwit our immune response? We have shown that, as children begin to develop antibodies to parasites, the malaria parasite changes its tactics to adapt to our defences.”

The researchers at the KEMRI-Wellcome Trust Programme studied malaria parasites in blood samples from 217 Kenyan children with malaria. They found that a group of genes coding for a particular class of PfEMP1 molecule called Cys-2 tended to be switched on when the children had a low immunity to the parasite; as immunity develops, the parasite switches on a different set of genes, effectively disguising it so that immune system cannot clear the infection

Dr Warimwe and colleagues also found an independent association between activity in Cys-2 genes and severe malaria in the children, suggesting that specific forms of the molecule may be more likely to trigger specific disease symptoms. This supports a previous study in Mali which suggested that the same class of PfEMP1 molecule was associated with cerebral malaria.

The findings could suggest a new approach to tackling malaria, in terms of both vaccine development and drug interventions, argues Dr Bull.

“If there exists a limited class of severe disease-causing variants that naturally-exposed children learn to recognise readily, this opens up the possibility of designing a vaccine against severe malaria that mimics an adult’s immune response, making the infections less dangerous. But this would still be an enormous task.

“Similarly, if we can establish what the particular class of molecules are doing, then we may be able to develop a drug to modify this function and relieve symptoms of severe disease.”

Story Source:

Adapted from materials provided by Wellcome Trust, via EurekAlert!, a service of AAAS.

http://www.sciencedaily.com/releases/2009/11/091130151325.htm

Gene-Testing Machine for Doctors

Simple testing: This disposable cartridge can detect genetic variations from blood samples. The circles lining the top and bottom are loaded with reagents for different chemical reactions. DNA is isolated from white blood cells and captured on a glass slide within the cartridge.   Credit: Nanosphere

A new device rapidly analyzes blood for medically relevant genetic variations.

By Emily Singer

A desktop instrument recently approved by the U.S. Food and Drug Administration might finally bring pharmacogenomic testing–the use of a patient’s genetic information for drug prescription decisions–to the mainstream. The device, made by Nanosphere, a startup based in Northbrook, IL, can, in a matter of hours, detect genetic variations in blood that modulate the effectiveness of some drugs. Dubbed Verigene, the technology employs a combination of microfluidics and nanotechnology, housed in a single plastic cartridge, to pull DNA from a blood sample and then screen it for the relevant sequences.

“We believe the benefit of our system is that this simple cartridge format could be run in any hospital, even a doctor’s office,” says William Moffitt, chief executive at Nanosphere. “We’re moving complex testing to the point of patient care.” Moffitt says Verigene is the first nanotechnology-based microfluidics product capable of analyzing DNA directly from a blood sample.

People can respond to drugs very differently, thanks in part to commonly occurring genetic variations in enzymes that metabolize some of the mostly highly prescribed compounds, such as heart medicines, pain medicines, and antidepressants. While doctors have widely adopted pharmacogenomic testing for prescribing some cancer drugs, such testing hasn’t yet taken hold for many other drugs whose effectiveness is modulated by genetics, including those for HIV, pain control, and epilepsy. The technology needed to detect these variations in patients has been available for years, but the process is often time-consuming and expensive. Physicians typically must send patients’ saliva or blood samples to a central lab, where the DNA is isolated, amplified, and analyzed. That process can take days or weeks.

“In some cases, it doesn’t matter if it takes a week to get a result. But in some cases we would like to have the information to choose a drug during the office visit, when the patient is right there,” says Howard McLeod, director of the Institute for Pharmacogenomics and Individualized Therapy at the University of North Carolina, Chapel Hill. “That way we can say, this drug is the one your DNA says will most likely be beneficial.”

The anticoagulant warfarin, for example, is frequently prescribed to prevent blood clots. But people metabolize the drug differently, meaning patients must be carefully monitored to make sure they don’t suffer dangerous bleeding. The FDA changed the drug’s label in 2007 to note that two specific genetic variations affect a patient’s sensitivity to the drug, but broad gene testing has not yet caught on. “Currently, available genotyping tests for warfarin pharmacogenomics require isolation of DNA from blood and testing in a molecular diagnostics laboratory certified for high-complexity testing,” says Karen Weck, director of the molecular genetics laboratory at the University of North Carolina, Chapel Hill.

Nanosphere is developing a test that can detect these variations in blood samples in an hour or two. A patient’s blood is injected into a disposable cartridge, which holds a glass slide dotted with DNA. The plastic frame also houses a system of microfluidics chambers containing the reagents for a number of chemical reactions. When the cartridge is inserted into the Verigene instrument, mechanical valves and air pressure mix the reagents in different chambers, triggering a series of reactions.

Story Continues – http://www.technologyreview.com/biomedicine/24042/

Abbott’s deal with Teva keeps generic TriCor off the market yet again

Melly Alazraki

The case of Abbott Laboratories’ (ABT) cholesterol drug TriCor is quite interesting. The drug has been a blockbuster, and it has been under patent protection for decades. That’s right, decades. Now, Abbott has managed to seal a deal with generic drug maker Teva Pharmaceuticals Industries Ltd. (TEVA) that would stave off generic competition for TriCor — yet again — until March 2011 at least.

How did Abbott manage to keep TriCor under patent protection all these years? The story begins back in the 1960s, when the drug was discovered by the French company Fournier. It began selling the product in Europe in 1975 and Abbott licensed it in 1998. The drug’s underlying patent had expired by that time, but Abbott, which earns more than $1 billion in annual sales from the drug, found a way to patent it again … and again … and again.

In 1999, a generic drug company that was later acquired by Teva was about to introduce a generic version of TriCor. Abbott sued for patent infringement and the two have been in court ever since. To protect its patent, Abbott used a tactic favored by many pharmaceutical companies in their scrambles to keep drugs under patent protection: Abbott patented a new formulation for TriCor by changing the type of pill (from capsule to tablet) and the dosage. In doing so, it prevented pharmacists from automatically switching prescriptions for TriCor to a generic version. Teva’s plans for the generic version were derailed and this whole scenario repeated itself in 2002.

While Abbott denied any wrongdoing, it did agree to pay $184 million to settle litigation brought by state attorneys general and private entities alleging antitrust and unfair competition claims in connection with the sales of TriCor.

The SEC filing from Monday that disclosed the settlement with Teva didn’t disclose many details. What we know is that the deal involves the TriCor 145-milligram tablet and that it postpones the sale of a generic version of TriCor until March 28, 2011, at the earliest. Fournier S.A. also agreed to the deal. Also, under certain defined circumstances, Teva may not receive rights until July 1, 2012.

Another Loophole, Another Profit Booster

Meanwhile, last year, the Food and Drug Administration approved TriLipix, a new branded Abbott drug that is similar to TriCor but is approved for use in combination with statins, a popular class of cholesterol-lowering drug. So now Abbott is scrambling to switch patients to TriLipix from TriCor before generic versions of TriCor appear.

If you think that something smells funny here, you’re not alone. While Abbott makes essentially cosmetic changes to TriCor that allow it to somehow convince the FDA that it’s a new drug which warrants new patent protection, the ones who are left to foot the bill for the more expensive, branded drug seem to be, as always, the patients and the taxpayers.

Abbott is not paying Teva to delay the introduction of a generic version, Kelly Morrison, a company spokeswoman told DailyFinance. “There is no payment/commercial agreement as part of this — this is a pure licensing agreement,” she said, adding that “this allows Abbott to obtain certainty for our product and avoid risk and costly litigation around our patents.” But what Teva gets out of the deal to induce it to agree to this arrangement is not clear.

Many pharmaceutical companies have paid generic makers over the past decade to delay generics. The Federal Trade Commission doesn’t look kindly on such “pay-for-delay” deals: The practice ends up costing U.S. consumers $3.5 billion a year — $1.2 billion of which is paid by the government, FTC chief Jon Leibowitz said in June.

Questions of generics aside, some doctors are growing skeptical about the benefits of TriCor, with published studies showing that it failed to definitively reduce heart attacks and related heart diseases, while possibly causing kidney problems. Abbott defends the drug’s efficacy and safety.

Abbott has been able to fend off most problems when it comes to TriCor — to the delight of its shareholders. But perhaps it’s time someone took a closer look not just at generic delaying practices but also at FDA’s rulebook when it comes to issuing patents on barely modified drugs. The market could have had a generic version of TriCor since 1999. At $1 billion a year in sales, that’s a big chunk of savings that patients, insurers and taxpayers have missed out on.

http://www.dailyfinance.com/2009/12/01/abbotts-deal-with-teva-keeps-generic-tricor-off-the-market-yet/

Caterpillar Flu Vaccine Delayed

Growing immunity: These images show insect cells growing without virus genes (top) and with virus genes (bottom). Scientists say the approach can produce 100,000 doses of vaccine per week, and can be adapted for different viruses, including H1N1 (swine flu).  Credit: Protein Sciences

The FDA wants further evidence that the novel approach is completely safe.

By Jennifer Chu

A new method of making flu vaccines is faster, more efficient, and more robust than the one that has been in use for the last 50 years. It has the potential to scale up rapidly, to deal with new strains of influenza such as this year’s H1N1, and to help stem a pandemic tide. However, a U.S. Food and Drug Administration advisory panel voted in late November not to approve the technology, which involves growing key vaccine ingredients inside caterpillar cells instead of in chicken eggs, as is currently done. The FDA says that the company behind the new approach, Protein Sciences, based in Meriden, CT, needs to test it further before the method can be approved for use in the United States.

Jose Romero, chief of pediatric disease at Arkansas Children’s Hospital and a member of the 11-person FDA panel, says that, while the company has more to do in order to prove safety, the cell-based technology shows considerable promise.

“This type of technology is going to move traditional influenza vaccinology into the 21st century,” says Romero. “We recognize that there may come a day when a strain does arrive that cannot be supported by growth in traditional egg-based technology, and this and other cell-based technologies can breach that problem and provide us with another avenue for developing vaccines.”

Today’s egg-based vaccine technology is slow and unwieldy, requiring at least six months’ of production time and millions of eggs to supply enough doses for a regular flu season. If a new virus appears unexpectedly, the antiquated system wouldn’t be able to gear up fast enough to produce a new vaccine, many experts agree. What’s more, if the virus itself were derived from birds, it might reduce the supply of eggs, hampering the country’s main means of vaccine production.

For the past decade, Protein Sciences, along with a number of other companies, has been looking to cell-based vaccines as a more efficient and robust alternative. Instead of growing viruses in chicken eggs, researchers inject virus strains into insect cells. Both the virus and the cells then grow and multiply quickly in bioreactors. Scientists break the cell walls and harvest a key protein, called hemagglutinin, produced by the virus. This protein, found on the influenza virus’s outer surface, is responsible for binding to cells in the body, causing a viral infection. Scientists purify and inactivate the harvested protein so that it can stimulate an immune response without causing an infection. The protein is the main ingredient in a vaccine.

Protein Sciences’ technology is a slight variation on the conventional cell-based approach. Instead of growing live viruses, the company replicates viral DNA within cells. The genes for hemagglutinin are extracted from a dead flu virus and injected into baculovirus–a virus that infects a caterpillar called the armyworm. The baculovirus is then injected into ovary cells isolated from the armyworm. In a bioreactor, the virus eats away at cells, replicating DNA and producing hemagglutinin.

“Because the starting material is a DNA sequence, it eliminates a lot of steps you have to go through, because the flu virus itself is not part of this production process,” says John Treanor, a medical advisor to the company and professor of microbiology and immunology at the University of Rochester Medical Center in New York. “You also don’t have concerns of workers getting infected, versus using a growing virus.”

Treanor headed four clinical trials to test the vaccine for effectiveness against seasonal flu. The trials compared the effects of the company’s vaccine against a conventional one in 3,231 people aged 18 and older.

The company presented its results to the FDA advisory board. While the new vaccine was found to protect against seasonal flu symptoms in those 18 to 49, it was not possible to draw significant conclusions for older participants. Several older subjects suffered from facial swelling after receiving the vaccine, and one developed a temporary paralysis on one side of the face. This might have been a preexisting condition, but researchers couldn’t be sure if the condition was independent of the vaccine. “When you have one case, it’s hard to know,” says Treanor.

The FDA panel recommended that the company expand the patient group to determine whether the vaccine is safe in a larger, older population.

Other companies seeking FDA approval for similar cell-based vaccines include Novartis, which opened a vaccine manufacturing plant in North Carolina this week and plans to produce vaccines from dog kidney cells.

FluGen, a vaccine company based in Madison, WI, has also entered the race. It is growing flu virus in manipulated hamster ovary cells–a cell line that has already been approved by the FDA for producing drugs to treat rheumatoid arthritis. FluGen is a little behind its bigger competitors, but CEO Paul Radspinner says he will take a lesson from Protein Sciences’ experience when it comes time to seek FDA approval. “Maybe it’s a learning point,” says Radspinner. “We’ll be very careful with where we go with clinical trials where there’s a database of patients coming through, and [make sure] that preexisting conditions are being noted.”

http://www.technologyreview.com/biomedicine/24031/

Identifying Anticancer Immune Cells

Cell mates: This microfluidics chip (top) contains 1,536 minute wells, each designed to force contact between two fluorescently labeled cells. An immune cell and a tumor cell are forced into contact inside a single well of a microfluidics chip (bottom). The setup allows researchers to identify, isolate, and study immune cells with particularly potent anticancer characteristics.  Credit: COCHISE Project

A new biosensor can spot potent cancer-killing immune cells.

By Lauren Gravitz

Scientists have long known that the human immune system has a method for detecting and destroying precancerous cells. But finding the cells behind this defense mechanism in order to study and perhaps even mimic them has proved quite the challenge. Since the malignant precancerous cells are eradicated before we even know they exist, identifying the cells that killed them seemed nearly impossible. Now European researchers have built a microfluidic biosensor that traps single immune cells together with single tumor cells, allowing the researchers to pick the most potent of these cancer killers out of a crowded field.

The project, called Cell On CHIp bioSEnsor (COCHISE), was initiated by microsystems engineer Roberto Guerrieri at the University of Bologna, Italy. Guerrieri noticed that immunologists had no way to identify and isolate those rare immune cells, or lymphocytes, with antitumor properties–only about one in every 1,000 immune cells has such properties.

Together with postdoctoral researcher Massimo Bocchi, Guerrieri created a microfluidics platform with an array of 1,536 microwells. In each well, electric fields force contact between a fluorescently labeled tumor cell and a labeled immune cell. An automated system then scans the array and detects wells in which the tumor cell’s color has disappeared, thereby identifying the lymphocytes that are likely most effective against the leukemia and lymphoma cancers they tested.

The researchers then collect the individual cells that have triumphed over the tumor cells andprovide them to immunologists for study and propagation. “Analyzing a cell we know is active is a large step for research, because you can correlate expression of cytokines or gene expression,” Bocchi says. “You can then identify genetic properties that are probably responsible for the cell being active against the tumor.” He notes that this could one day be used to find new drugs to fight the disease.

Guerrieri and his colleagues are also working to clone entire cell lines from these single, potent lymphocytes. They plan to see if the resulting daughter cells maintain the same anticancer properties. If so, such an approach could be useful for developing cancer vaccines based on a transplant of a patient’s own lymphocytes, the researchers say.

As far as the biosensor is concerned, “the design itself is not really new,” says Luke Lee, director of the Biomolecular Nanotechnology Center at the University of California at Berkeley. Others have developed similar designs, although Lee notes that none are as user-friendly as the COCHISE system. Unlike the other devices, Lee says, the biosensor devised by Guerrieri and Bocchi and their collaborators offers a way to cleanly deliver cells to the chip and manipulate them. “Most demonstrations aren’t as clean as this,” he says.

Article Continues – http://www.technologyreview.com/biomedicine/24020/

Big Hope for Tiny Particles

Nanotechnology-based drug delivery offers new treatment options for deadly pancreatic cancers.

By Erika Jonietz

Nanoparticles that deliver two or more drugs simultaneously can significantly shrink pancreatic cancer tumors and also reduce its spread, say researchers at Massachusetts General Hospital. Tayyaba Hasan, who is also a professor of dermatology at Harvard Medical School, led the development and testing of two “nanocells.” These nanocells combine light-based therapy with molecules that inhibit the growth of cancer cells or of the blood vessels that feed them.

Though the particles have only been studied in mice so far, the cancer-research community is excited. Pancreatic cancer remains one of the deadliest and hardest cancers to treat; mortality rates have changed very little in the last 30 years. After diagnosis, patients tend to live only six months, and less than 5 percent survive for five years. “In terms of a patient population, there is very little we can do for them once we find the cancer,” says Craig Thompson, director of the Abramson Cancer Center at the University of Pennsylvania.

Hasan and two research fellows in her lab, Prakash Rai and Lei Z. Zheng, presented their initial results on November 17 at the International Conference on Molecular Targets and Cancer Therapeutics, held jointly by the American Association for Cancer Research, the U.S. National Cancer Institute (NCI), and the European Organization for Research and Treatment of Cancer.

The team’s first type of nanocell is designed to effectively starve tumors by cutting off their blood supply. They trapped a photosensitive drug called verteporfin, which creates toxic oxygen radicals when exposed to specific wavelengths of light, inside solid polymer nanoparticles. Those nanoparticles were then encapsulated in lipid particles along with bevacizumab, an antibody that specifically inhibits the growth of new blood vessels by blocking a protein called VEGF. Both verteporfin and bevacizumab are already approved by the U.S. Food and Drug Administration. Bevacizumab is approved for the treatment of advanced cancers of the colon, breast, lung, and kidney; it’s marketed by Genentech as Avastin. Verteporfin is used to eliminate abnormal blood vessels in wet-form macular degeneration. It’s sold as Visudyne by Novartis.

In a previous small-scale clinical trial, verteporfin alone increased the median survival of pancreatic cancer patients from six months to nine months. Adding Avastin, however, did not increase survival time–possibly because the Avastin killed off the tumor’s blood vessels, making it difficult to get enough of the photosensitive drug to the cancer.

In contrast, when the nanocells are injected intravenously, they deliver both drugs directly to the inside of cancer cells. Blood vessels in normal tissue are impermeable to the nanoparticles, but blood vessels in tumors are “leakier,” with much larger pores that allow the nanoparticles to pass through. As a result, the nanoparticles accumulate inside tumors and deliver more of their payload to the cancer cells than to healthy cells. The nanocells provide a higher effective dose of drug to the tumors as well as fewer side effects because the researchers used a lower dose of both drugs than usual.

The team implanted human pancreatic cancer cells in mice and allowed tumors to grow. They then injected the mice with a single dose of the nanocells and exposed the tumor to long-wavelength light. Mice given this single treatment showed a greater reduction in their tumor size than mice treated with either drug alone. The mice treated with the nanocells also had at least two times fewer metastases to the liver, lungs, and lymph nodes. “Injecting these things as separate entities is not as effective as combining them into one construct,” says Hasan.

Hasan believes that’s because the nanocells actually fuse with the tumor cells and deliver the Avastin inside the cell, instead of just to the outside. And though Hasan’s lab has not done any toxicity studies, she hopes that the nanocells’ preferential accumulation inside of tumors may decrease the drug’s side effects, which can be quite dangerous. As many as 30 percent of patients receiving Avastin suffer cardiovascular side effects, including dangerously high blood pressure, stroke, and heart failure.

Shiladitya Sengupta, an assistant professor of medicine and health sciences and technology at Harvard Medical School, calls the results of Hasan’s mouse experiments “dramatic.” He says, “In the context of pancreatic cancer, [the results are] outstanding, because there’s no therapy.”

Sengupta did not participate in Hasan’s research, but he originated the idea of drug delivery using nanocells. Technology Review recognized him for this idea with a 2005 TR35 award. He cofounded Cerulean Pharma to commercialize the nanocell platform and other nanopharmaceutical delivery methods. But one tricky aspect of the technology is that it must be individually optimized for every new combination of drugs, he notes.

Hasan’s team has already developed a second nanocell designed to prevent pancreatic cancers from developing resistance to chemotherapy, a very common problem. Other researchers have identified two proteins, EGFR and MET, as particularly important in the development and growth of pancreatic cancer. In fact, in cancer cell lines in the lab, when biologists block EGFR, the cells increase their production of MET, and vice versa. So to better control the tumors, Hasan’s team set out to target EGFR and MET simultaneously, while again hitting the tumor with light to increase the effectiveness of the treatment.

This second nanocell required a more sophisticated design. Rai started with a small molecule called PHA-66572, which inhibits the MET protein, and confined it in the same sort of solid polymer nanoparticle used in the first nanocell. He then surrounded those nanoparticles with cetuximab, an antibody that blocks EGFR. Finally, he incorporated Visudyne into a lipid sphere that he used to encapsulate these two layers.

Zheng says that tumors shrank dramatically in mice that had been implanted with pancreatic cancers and then given a single injection of the nanocells followed by light therapy. He is still measuring the effects on metastasis, but since the MET protein is active in most cancers that have metastasized (not just pancreatic cancer), the researchers are optimistic that the growth-factor nanocells will significantly decrease the number and size of metastases as well.

Zheng says that these results are particularly encouraging because of the apparent reduction in toxicity of the drugs. Pfizer developed PHA-66572 specifically to block MET in cancer cells, but it proved so toxic that the company abandoned the drug. In contrast, Zheng says that the animals that he gave the nanocell maintained normal activity levels and didn’t lose weight.

Hasan hopes that both nanocells will be tested in pancreatic cancer patients within just a few years. Because Avastin and Visudyne are already FDA-approved, their two-part nanocell will likely be the first tested, probably in about two years, but perhaps as soon as a year from now, she says.

The NCI is already conducting toxicology tests of the Avastin-Visudyne nanocell as part of a new drug application to the FDA. The growth factor nanocell should enter the clinic “soon after,” Hasan says. The key is finding the best MET inhibitor, and Hasan says that other researchers are already testing several promising candidates.

http://www.technologyreview.com/biomedicine/24022/

A Cancer-Fighting Implant

Cancer killer: A cross section of a polymer matrix designed to prime the immune system against cancer. Immune cells crawl through the pores and are activated by chemical signals and tumor molecules.  Credit: Edward Doherty, Omar Ali and Microvision Labs

A polymer disc shrinks tumors in rodents by eliciting an immune attack.

By Emily Singer

In a new approach to fighting cancer, scientists from Harvard University have engineered an implantable disc designed to attract immune cells and prep them to attack tumors. Mice with melanoma tumors were much more likely to survive if they’d been implanted with the device, and tumors disappeared in up to half of the vaccinated animals, according to research published today in the journal Science Translational Medicine. Researchers believe that the implant elicits a broader immune response than traditional vaccines, and may therefore prove more effective. A startup called InCytu, based in Lincoln, RI, is now developing the technology for human testing.

A number of vaccines for treating different types of cancer are currently being tested in clinical trials, though none has yet been approved by the U.S. Food and Drug Administration. Unlike traditional vaccines, therapeutic cancer vaccines are designed to halt or reverse the course of the disease after it has developed. Gardasil, Merck’s vaccine against the human papillomavirus, is considered a preventative cancer vaccine and acts in a similar way to traditional vaccines. It helps prevent the development of cervical cancer by stopping viral infection–but it cannot treat existing cervical cancer.

While cancer vaccines come in several variations, the general approach is to trigger the immune system to recognize and destroy cells bearing a cancer-specific marker. The immune system can be tuned to cancer cells by injecting patients with specific molecules linked to different types of cancer, or by injecting irradiated cancer cells. Scientists have also tried to enhance this process by training the immune cells in a controlled environment outside the body–the cells are isolated from the patient’s blood and exposed to cancer-specific molecules. The primed immune cells are then injected back into the patient, where they travel to the lymph nodes and trigger an immune response against the cancer.

A number of vaccines for treating different types of cancer are currently being tested in clinical trials, though none has yet been approved by the U.S. Food and Drug Administration. Unlike traditional vaccines, therapeutic cancer vaccines are designed to halt or reverse the course of the disease after it has developed. Gardasil, Merck’s vaccine against the human papillomavirus, is considered a preventative cancer vaccine and acts in a similar way to traditional vaccines. It helps prevent the development of cervical cancer by stopping viral infection–but it cannot treat existing cervical cancer.

While cancer vaccines come in several variations, the general approach is to trigger the immune system to recognize and destroy cells bearing a cancer-specific marker. The immune system can be tuned to cancer cells by injecting patients with specific molecules linked to different types of cancer, or by injecting irradiated cancer cells. Scientists have also tried to enhance this process by training the immune cells in a controlled environment outside the body–the cells are isolated from the patient’s blood and exposed to cancer-specific molecules. The primed immune cells are then injected back into the patient, where they travel to the lymph nodes and trigger an immune response against the cancer.

The polymer is also packed with small fragments of genetic material designed to mimic bacterial DNA. These fragments signal to the dendritic cells that a foreign invader is present. Also present are ground-up pieces of the patient’s tumor, which show the cells what to attack. The dendritic cells pick up these molecules as they move through the scaffold. The cells then travel to the lymph nodes, where they introduce the target molecules and generate an immune response. “When the implant is in the body, the immune system sees it as dangerous material and attacks it,” says Tarek Fahmy, a bioengineer at Yale University who was not involved in the research.

In mice with established melanoma tumors, the vaccine significantly slowed the growth of the tumors and increased animals’ survival time. In addition, tumors completely disappeared in 20 to 50 percent of animals given two vaccinations, depending on how long the tumors had been growing. Researchers say this is significant, given that most cancer vaccines considered to be effective in rodents have been shown to prevent formation of tumors rather than to diminish established tumors. However, it’s difficult to compare different rodent models of cancer, which can vary widely.

The implant’s effectiveness may lie in the immune response that it triggers, says Mooney. It appears to generate the formation of different types of dendritic cells, which may make the immune response more potent. It also appears to dampen a part of the immune system that typically neutralizes the response once it’s been activated–maintaining an activated immune system might be important in preventing tumors from recurring. “That is very novel and extremely important for cancer immunotherapy,” says Fahmy.

As is often the case with new cancer treatments, it’s difficult to predict how well the findings will translate to humans. A number of cancer vaccines have shown success in animal models and then failed in human clinical trials.

http://www.technologyreview.com/biomedicine/24013/

Vaccine disc: The disc-shaped implant is smaller than a dime.  Credit: InCytu

Measuring and Modeling Blood Flow in Malaria

When people have malaria, they are infected with Plasmodium parasites, which enter the body from the saliva of a mosquito, infect cells in the liver, and then spread to red blood cells. Inside the blood cells, the parasites replicate and also begin to expose adhesive proteins on the cell surface that change the physical nature of the cells in the bloodstream.

Experiments show that infected red blood cells are stiffer and stickier than normal ones — in the later stages of the disease, up to 10 times stiffer. They also tend to adhere to the endothelial cells lining the vasculature, affecting the normal blood flow. This explains some of the common symptoms of malaria, such as anemia and joint pain.

Sticking to the walls of blood vessels is a survival mechanism for the parasite. In order to develop completely, it needs several days inside a red blood cell. Even though parasitized cells are nearly invisible for the immune system, they may be destroyed in the spleen while circulating freely in the bloodstream.

Doctoral student Dmitry Fedosov and Brown University professor George Karniadakis are studying how malaria infections affect the physical properties of red blood cells, and alter normal blood flow circulation. In particular, they examine an increase in blood flow resistance, and dynamics of infected cells in the bloodstream.

They also monitor the mechanical properties of infected red blood cells by measuring membrane temperature fluctuations, and through the response of a “microbead” that is attached to the cell and twisted. The measured properties are then used in modeling the flow of red blood cells in people infected with malaria. They also collaborate with the group of professor Subra Suresh at MIT, who obtain experimental measurements of the properties and the flow of healthy and infected cells.

“Our model predicts the dynamics of malaria-infected RBCs in the bloodstream, which anticipates the possible course of the disease,” says Fedosov.

Recently they found that temperature fluctuations of infected red blood cell membranes measured in experiments are not directly correlated with the reported cell properties, hence suggesting significant influence of metabolic processes. They measured an increase in resistance to blood flow in the capillaries and small arterioles during the course of malaria and found that parasitized red blood cells have a “flipping” motion at the vessel wall that appears to be due to stiffness of the infected cells. The developed models will aid to make realistic predictions of the possible course of the disease, and enhance current malaria treatments.

The talk “Multiscale modeling of blood flow in cerebral malaria” by Dmitry Fedosov, Bruce Caswell, and George Karniadakis is on November 22, 2009.

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Adapted from materials provided by American Institute of Physics, via EurekAlert!, a service of AAAS.

http://www.sciencedaily.com/releases/2009/11/091123083700.htm

New Device Implanted by Surgeons Help Paralyzed Patients Breathe Easier

Physicians at UT Southwestern Medical Center soon will begin implanting a new device designed to improve breathing in patients with upper spinal-cord injuries or other diseases that keep them from breathing independently.

UT Southwestern University Hospital — St. Paul is only one of only two sites in Texas and one of 25 in the country currently equipped to implant the device, called the NeuRx Diaphragm Pacing System.

The device is designed to give patients more freedom and to help slow respiratory decline. Patients who have diseases or injuries that affect breathing muscles, such as the diaphragm, are more prone to lung infections because of their weakened ability to inhale and exhale sufficiently, said Dr. Michael DiMaio, associate professor of cardiovascular and thoracic surgery at UT Southwestern.

“Patients who have high-level spinal-cord injuries are unable to breathe efficiently because the nerve signals no longer function,” Dr. DiMaio said.

The diaphragm separates the abdomen and chest cavity and contributes to 80 percent of respiration. Nerve signals from the brain tell it when to expand and contract. When it expands, pressure inside the chest is reduced and air rushes into the lungs. When the diaphragm relaxes, the lungs and chest wall push air out.

People with spinal-cord injuries that interfere with breathing are typically placed on external mechanical ventilators that support breathing through positive pressure via a tube placed directly into the airway through the front of the throat.

The implantable device, manufactured by Ohio-based Synapse Biomedical, was approved by the Food and Drug Administration in 2008. The NeuRX system includes four electrodes that are implanted directly into the diaphragm. Electrical signals from an external control device induce impulses from the phrenic nerve, which runs from the spine to the diaphragm. Once those signals reach the electrodes in the diaphragm, the muscle is stimulated to expand and contract. This action more closely simulates normal breathing than external ventilators.

“This device has some advantages over traditional ventilators,” Dr. DiMaio said. “Patients have more mobility because they don’t have an external ventilator to carry around, and the surgery to implant the device is less invasive than previous treatments.”

Researchers said they hope the new device can improve quality of life and decrease incidents of infections that can affect patients who are on external ventilators. Prior generations of phrenic nerve stimulators were inserted by making an incision in the neck and chest. Electrodes were then placed directly on the nerve, rather than the diaphragm.

“Although phrenic nerve stimulation as a way to induce breathing in these patients isn’t a new concept, we think the NeuRX will alleviate some symptoms present with previous stimulators,” said Dr. Jose Viroslav, professor of internal medicine at UT Southwestern and pulmonary and critical care specialist. “One of the problems that arose before was scarring and fatigue of the phrenic nerve. This stimulator is placed on the diaphragm, and the pulses are more diffuse.”

Dr. Viroslav said another major advantage with the NeuRX device is that it helps with speech.

“Patients on diaphragmatic pacers have more of a normal ventilation, and their vocal cords are not bypassed therefore they can talk,” he said. “Breathing with the diaphragm is normal, and if you can do it with implantable electrodes, you are closer to breathing normally with the advantages of speech, less infection, and more mobility.”

Patients who are interested in the NeuRX device should first consult with their physician to determine whether they might be eligible.

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Adapted from materials provided by UT Southwestern Medical Center.

http://www.sciencedaily.com/releases/2009/11/091125135128.htm