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Chemotalk NewsletterChemotalk Newsletter, Vol. 84: April 1, 2015 Good morning, Spring!...Finally! Here goes.... NEW WAY TO SORT CELLS WITHOUT LIMMITATIONS OF TRADITIONAL METHODS A team of Stanford University School of Medicine researchers has come up with a new way of analyzing individual cell types by applying advanced mathematical analysis to the cells' contents. The method is analogous to analyzing a smoothie to find what fruits went into making it, the researchers say. A paper describing the method, called Cibersort, was published in Nature Methods. Analyzing and sorting individual cells according to the proteins they display on their surfaces is an essential part of stem cell science and CANCER research. By analyzing these proteins, known as cell surface markers, scientists can figure out what kind of cells they are dealing with and see how the cell samples, taken from an animal over a period of time, change. With cancer, the presence or absence of certain cell markers can make a huge difference in a patient's prognosis and what treatments will be most effective. But many kinds of tissue can't be analyzed easily or accurately using current methods of cell sorting, hampering scientists' ability to do research and clinicians' ability to find the most effective therapies for cancer and other diseases. "The basic problem is that we often want to count cell populations in tissues, but we rely on methods that require tissues to be collected and stored, then separated into individual cells or sliced into sections, and then labeled with antibodies to specific markers," said Ash Alizadeh, MD, PhD, assistant professor of medicine and the senior author of the paper. "Each of these steps has limitations." How Cells Are Sorted Decades ago, Stanford researchers were among the world's leaders in developing a method for analyzing cells called flow cytometry. With this method, tissues are first separated into individual cells and exposed to fluorescently labeled antibodies that attach to particular cell surface markers. Then a few cells at a time, in tiny drops of water, are passed in front of a laser that excites the fluorescent antibodies and an optic sensor that counts each type of cell in the drop. In some machines, the different kinds of cells can be sorted into various containers. The standard method of cell sorting requires breaking up tissues, or disaggregating them, into individual cells, Alizadeh said. This is a rough process that destroys certain cell types and renders some tissues useless for study. In addition, the traditional method of preserving medical samples makes it impossible to process them in this way, he noted. Also, fluorescently labeled antibodies must be produced for each specific cell protein in which the scientists are interested. Antibodies may not be available for some proteins, he said. The solution the researchers came up with is to sort not the cells, but their contents. "We were asking, ŒCan you take a tissue, blend it up, look at the contents and tell what kinds of cells they came from?'" Alizadeh said. Reconstructing The Cellular ŒSmoothie' In developing the new method, Alizadeh and his colleagues focused not on the protein cell surface markers, but on the RNA on which those proteins were patterned. Postdoctoral scholar Aaron Newman, PhD, devised a computer algorithm to reconstruct the type and number of original cells based on the RNA contents of the mixture of all the cells. "It's like reconstructing a smoothie," said Newman, a lead author of the paper. "You know it has a lot of different kinds of fruit in it, but you don't know right away how many of each type. However, you might know that strawberries had a certain amount of sugar and red coloring, while oranges have a different amount of sugar, orange coloring and more tartness. If you analyze each of these qualities, you can reconstruct how many of each kind of fruit went into making the smoothie." In addition to avoiding the problems inherent in breaking up tissues into single cells, researchers using this method won't need fluorescently labeled antibodies for the cell surface markers they are looking for, he said. Some of the most exciting recent advances in the treatment of cancer involve the use of novel drugs that engage immune responses in patients to fight the disease. These drugs often target rare and dormant populations of immune cells that reside within tumors. While some of these drugs can be dramatically effective for patients with very different tumor types, not every patient benefits equally, and some tumor types appear not to respond to these new immune therapies. "A significant, ongoing effort is to find which immune cells mediate response and resistance to these drugs, to allow their more directed and precise use in a personalized fashion," said Alizadeh, who is also a member of the Stanford Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Cancer Institute. "If we apply Cibersort to cancer tissues, we think we will be able to see amazing things." Targeting Cancer Treatments If the researchers apply Cibersort to old tumor samples from patients whose clinical history is known, they may be able to learn what kinds of cells signal more or less deadly cancers. They may also learn what kinds of treatments work better or worse in various subtypes of cancer. This sort of information might be most important for the antibody cancer therapies. "There are early hints that it is very important to know about the presence of specific types of immune cells in the tumor before and after certain therapies are given, and how those cells change over time," Alizadeh said. * * * WHY DRUGS COST SO MUCH By Peter Bl. Bach Eli Lilly charges more than $13,000 a month for Cyramza, the newest drug to treat STOMACH CANCER. The latest medicine for LUNG CANCER, Novartis's Zykadia, costs almost $14,000 a month. Amgen's Blincyto, for LEUKEMIA, will cost $64,000 a month. Why? Drug manufacturers blame high prices on the complexity of biology, government regulations and shareholder expectations for high profit margins. In other words, they say, they are hamstrung. But there is a simpler explanation. Companies are taking advantage of a mix of laws that force insurers to include essentially all expensive drugs in their policies, and a philosophy that demands that every new health care product be available to everyone, no matter how little it helps or how much it costs. Anything else an we're talking death panels. Examples of companies exploiting these fault lines abound. An article in The New England Journal of Medicine last fall focused on how companies buy up the rights to old, inexpensive generic drugs, lock out competitors and raise prices. For instance, albendazole, a drug for certain kinds of parasitic infection, was approved back in 1996. As recently as 2010, its average wholesale cost was $5.92 per day. By 2013, it had risen to $119.58. Novartis, the company that makes the leukemia drug Gleevec, keeps raising the drug's price, even though the drug has already delivered billions in profit to the company. In 2001, Novartis charged $4,540, in 2014 dollars, for a month of treatment; now it charges $8,488. In its pricing, Novartis is just keeping up with other companies as they charge more and more for their drugs. They know we can't say no. But what if we didn't require insurance companies to cover all drugs? We can se the answer in Europe. May European countries say no to a handful of drugs each year, usually those that are both pretty ineffective and highly costly. Because they can say no, yes is not a guarantee. So companies have to offer their drugs at prices that make them attractive to these health care systems. A recent survey of cancer drug policies revealed you don't have to say no very often to get discounts for saying yes. Of the 29 major cancer drugs included in the study that are available in the United States, an estimated 97% and 86% are also available in Germany and France, respectively. As a consequence of the stand taken by those countries, prices in Europe for prescription drugs are 50% below what we pay, according to a McKinsey study from 2009. Gleevec costs $4,500 per month in Germany today, and $3300 per month in France, less than what Americans paid in 2001. Saying no, or even the threat, works to lower prices in the United States, too. But it's rare. In 2012, my hospital said we wouldn't give the COLON CANCER drug Zaltrap to our patients because it cost twice as much as another drug (Genentech's Avastin) that was just as good. When we refused to use it, the company realized that other cancer hospitals and doctors might follow, and halved its price nationwide. More recently, Express Scripts, a company that manages pharmacy benefits, showed that approval was no guarantee. It was therefore able to play to makers of treatments for hepatitis C off against each other. Express Scripts said yes to AbbVie's Viekira Pak (for the most common subtype, genotype 1 disease), and said no to Gilead's Sovaldi and Harvoni. Another pharmacy benefit program, CVS Caremark, played it the other way, closing out AbbVie and choosing Gilead. Either way, the lesson is that Express Scripts, once it showed it could say no, got AbbVie to discount its product. It isn't saying how much, but Steve Miller, a senior executive, said it had "significantly narrowed the gap between prices charged in the United States and western Europe." Sounds like the kind of progress we need. You might worry about patients being harmed through these moves But we rejected Zaltrap knowing it was no better than the alternative. Express Scripts an CVS Caremark played the two drugs manufacturers off against each other because both manufacture effective treatments. The industry night argue that drug spending is only 10% of all health care spending, but that 10% equals around $200 billion per year. More important, the costs of high-priced drugs are being passed on to patients. Lilly's drug Cyramza will cost the average Medicare patient $2,600 per moth without supplemental insurance. That's more than most Medicare-age people earn each moth, before taxes. Actually, high prices get passed on to us all, either through individual costs or insurance. That leaves us with two options. We can free insurers and government programs from the requirement to include all expensive drugs in their plans as we explain to the public that some drugs are not effective enough to justify their price. If we do this, we can be confident that manufacturers will lower their prices to ensure their ability to sell their products. Or we can piggyback on the gumption of bolder countries, and demand that policy makers set drug prices in the United States equal to those of Western Europe. Either approach would be vastly superior to the situation we have today. * * * VACCINEX PROVIDES AN UPDATE ON ITS VX15/2503 PHASE 1 CLINICAL TRIAL IN MULTIPLE SCLEROSIS PATIENTS Vaccinex, Inc. today announced the successful completion of a multicenter phase 1, randomized, double-blind, placebo-controlled, single ascending-dose safety and tolerability study in adult patients with MULTIPLE SCLEROSIS (MS). A total of 50 patients were enrolled in 1 of 5 cohorts (1, 3, 6, 10, and 20 mg/kg) to determine the safety and tolerability of VX15/2503 when administered IV in a single dose. VX15/2503 is a first in class, monoclonal antibody discovered, characterized, and successfully tested by Vaccinex in preclinical models of Multiple Sclerosis and Huntington's Disease. VX15/2503 was found to be well tolerated at dose levels of up to 20 mg/kg with no reports of treatment-related serious adverse events. No maximum tolerated dose (MTD) was determined and no dose-limiting toxicities (DLTs) were observed. Preliminary data suggests that the half-life of a single dose of antibody is 21 to 23 days at the 20 mg/kg dose level, and that saturation of the SEMA4D target receptor lasted for approximately 155 days. Detailed study results will be published in a peer reviewed medical journal. Vaccinex, Inc. is a privately held clinical-stage immunotherapy company engaged in the discovery and development of human therapeutic monoclonal antibodies to treat CANCER and neurodegenerative diseases, including multiple sclerosis and Huntington's Disease. * * * F.D.A. BACKS A LUNG CANCER THERAPY By Andrew Pollack The first immune-based treatment for LUNG CANCER won approval from the Food and Drug Administration, and it it could displace more conventional CHEMOTHERAPY for certain patients, at least. The drug, Opdivo, from Bristol-Myers Squibb, is one of a class of medicines that have electrified oncologists in recent years because they free the body's own immune system to attack tumors. Opdivo, also known as nivolumab, was approved last year to treat advanced cases of the skin cancer MELANOMA, but the approval for lung cancer is in some ways more significant. Lung cancer is the leading cause of cancer deaths by far, with 224,000 new diagnoses and nearly 160,000 deaths last year. That means approval to treat lung cancer could help more patients and also result I much larger sales for Bristol-Myers. The drug sells for about $12,500 a month. Also, while melanoma was known to be vulnerable to attack from the immune system, many scientists doubted this would be true for lung cancer. In one trial, lung cancer patients who received Opdivo lived a median of 9.2 months compared with 6.0 months for those who received docetaxel, the standard chemotherapy used for such patients. By another measure known as the hazard ratio, the risk of death was 415 lower for those who received Opdivo, according to the drug's label. that study was terminated early because the results were so strong. And the F.D.A. decision to approve the drug came from faster than analysts had expected, more than three moths before the agency's deadline. The approval was only for so-called SQUAMUS CELL CANCER, which accounts for about 30% of cases of NON-SMALL-CELL LUNG CANCER and is associated with smoking. Moreover, the approval was for second-line treatment for metastatic disease, meaning that patients must first try chemotherapy. Dr. Francis Cuss, head of research and development at Bristol-Myers, said the company hoped to have clinical trial results for NON-SQUAMOUS LUNG CANCER by the middle of the year. It is also studying Opdivo as a first-line treatment for metastatic lung cancer, meaning that it could be used before chemotherapy. Opdivo, which is given by intravenous infusion every two weeks, inhibits a protein known as PD-1, which acts as a brake on immune system cells. With the brake disabled, the immune cells can attack the cancer. In one lung cancer study, Opdivo significantly shrank tumors in only 15% of lung cancer cases, a fairly low rate compared with some chemotherapy drugs which kill cancer cells by poisoning them. Yet immune system drugs appear to prolong lives for some patients even when the tumors do not shrink so much. "We've said that overall survival is where we think the value is," Dr. Cuss said. In winning the lung cancer approval, Bristol-Myers beat out it rival Merck, which has a similar drug called Keytruda. Merck beat Bristol to market for the treatment of melanoma last year. Analysts say Merck could gain approval for its drug as a second-line treatment for both squamous and non-squamous lung cancer by the end of the year. Mark Schoenebaum, an analyst at Evercore 1S1, said in a note that the Opdivo approval "was the fastest I've seen in my 15-year career." He estimated sales of Opdivo for second-line use in squamous cell lung cancer could reach $1 billion to $1.5 billion a year in the United States and Europe. With approval for non-squamous lung cancer, that could expand to more than $4 billion, he said. * * * Until May...stay strong, be well. And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com. Elaine Jesmer
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