CAR T cells that are currently being tested to treat B-cell malignancies target a specific protein present on leukemia and lymphoma, but these immune cells cannot distinguish cancer cells from normal cells, explained Cooper. Even though such CAR T cells attack cancer cells and normal B cells alike, the side effects are manageable, which may not be the case with solid tumors. "Many proteins that are present on solid tumors may also be present on normal cells that are vital to the body. So, while recipients of CAR T cells can tolerate the loss of normal B cells, they cannot endure damage to vital structures if the engineered T cells inappropriately damage essential tissues. Because of this, CAR T-cell-based immunotherapy may not yet be entirely safe for patients with solid tumors," added Cooper.
In an interview, Cooper said, "The goal of the study was to make CAR-expressing T cells differentiate friend from foe. We wanted to provide CAR T cells an improved opportunity of targeting a protein that is overexpressed on a cancer cell and spare normal cells that may also have the same protein, but at lower levels.
"We think this provides an advance in the field of CAR T-cell therapy because until now the focus in terms of T-cell activation was on the intracellular portion of the CAR design, which led to the development of second- and third-generation CARs with different abilities to signal T cells. Our study has shown that another possibility is to tweak the extracellular portion of the CAR that docks with the tumor by adjusting its affinity for the target protein," said Cooper. This technology can be used to develop CAR T cells that can be fine-tuned to target other overexpressed cancer proteins besides EGFR, Cooper explained. "An important derivative of this study is that scientists can now tweak, or modulate, the affinity of a CAR T cell to meet the needs of a given tumor."
Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity
Hillary G. Caruso1,2, Lenka V. Hurton1,2, Amer Najjar1, David Rushworth1,2, Sonny Ang1, Simon Olivares1, Tiejuan Mi1, Kirsten Switzer1, Harjeet Singh1, Helen Huls1, Dean A. Lee1,2, Amy B. Heimberger3, Richard E. Champlin4, and Laurence J.N. Cooper1,2,*
Many tumors overexpress tumor-associated antigens relative to normal tissue, such as EGFR. This limits targeting by human T cells modified to express chimeric antigen receptors (CAR) due to potential for deleterious recognition of normal cells. We sought to generate CAR+ T cells capable of distinguishing malignant from normal cells based on the disparate density of EGFR expression by generating two CARs from monoclonal antibodies that differ in affinity. T cells with low-affinity nimotuzumab-CAR selectively targeted cells overexpressing EGFR, but exhibited diminished effector function as the density of EGFR decreased. In contrast, the activation of T cells bearing high-affinity cetuximab-CAR was not affected by the density of EGFR. In summary, we describe the generation of CARs able to tune T-cell activity to the level of EGFR expression in which a CAR with reduced affinity enabled T cells to distinguish malignant from nonmalignant cells.
GENEVA, N.Y. — Every spring, a host of unwelcome visitors descends on the Hansen farm in upstate New York. Diamondback moths blown in from the South threaten rows of cabbages to be sold for slaw and sauerkraut.
The moths can’t be fought off with a single insecticide. Workers must spray a series of chemicals throughout the growing season to keep the moths’ numbers in check.
“You have to rotate what chemical you use so you don’t get a buildup in resistance,” said Ed Hansen Jr., whose family has farmed the land for nearly a century. This adaptability, he said, makes the moths one of the worst pests to deal with each season.
At a university laboratory down the road, scientists are hoping to substitute sex for sprays. They have genetically modified thousands of diamondback moths, infusing them with DNA designed to kill female larvae. In August, the researchers began introducing the altered mothsinto outdoor cages in a field, where their mating habits will be monitored.
If the results are promising, the transgenic moths will be released into a small cabbage patch next summer. It would be the first experimental release on American soil of insects genetically engineered to self-destruct.
A plan to let similar transgenic mosquitoes loose in Key West has met with strong opposition amid fears about being bitten. But federal regulators seem to have few worries about the safety of the moth experiments.
“Our goal as a community is to reduce the amount of pesticides used in agriculture,” said Anthony Shelton, the entomologist running the experiments at the Cornell University Agricultural Experiment Station. “Why not use genetics to accomplish this?”
An invasive species, the diamondback moth was once a minor nuisance. It became an agricultural headache in the late 1940s as chemical pesticide use exploded. The moth, the first crop pest to evolve resistance to DDT, multiplied as feebler competitors died off.
Today, the pest is found where kale, broccoli, Chinese cabbage and other cabbage cousins grow. Hungry caterpillars that hatch from eggs laid on the plants cost farmers an estimated $5 billion a year worldwide. And the diamondback moth continues to adapt to new generations of pesticides. In Malaysia, it is immune to all synthetic sprays.
In the 1990s, scientists searching for alternatives to pesticides bombarded diamondback moths with gamma rays to sterilize them. This tactic had eradicated from the United States a parasitic fly larva called the screwworm; for decades, hordes of radiation-sterilized male flies were released in the wild, outcompeting fertile males and reducing the population.
But the diamondback resisted even radiation. So Oxitec, the British biotechnology company working with Dr. Shelton, found another way to sabotage diamondback reproduction. The company, an Oxford University spinoff, stitched together scraps of DNA from a virus and a bacterium to make a gene deadly to female insects.
A female larva harboring the gene is dependent on regular feedings of the antibiotic tetracycline to survive. Out in the wild, she dies long before reaching adulthood.
In a study by company scientists published in BMC Biology in July, male moths carrying the gene wiped out communities of normal moths living in small cages. Females mating with transgenic males had as many offspring as those coupling with unaltered males, but the female offspring died before being able to reproduce.
Only some of the male offspring inherited the synthetic gene, which tends to disappear after a few generations. So thinning the moth population required multiple waves of assault by fresh males bred in the lab.
Dr. Shelton’s outdoor cages, also stocked with wild moths, will test how well the genetically engineered males compete in a bigger arena. The release next summer into the field would take the technology one step closer to being used on farms.
The strategy has drawn criticism. Groups opposed to the use of genetically modified organisms worry that the protein made by the synthetic gene could harm wildlife that eat the moths.
“We would argue that more information should be collected,” said Helen Wallace, the director of GeneWatch U.K.
Haydn Parry, the chief executive of Oxitec, says the company addressed this concern and others in data submitted to the Department of Agriculture.
“We fed the protein to mosquitoes, fish, beetles, spiders and parasitoids,” he said. “It’s nontoxic.”
After weighing the evidence, the department decided the planned experiments would have no significant effect on the environment.
A public letter signed in June by the Northeast Organic Farming Association of New York protested any outdoor trials. The association cautioned that escaping moths could contaminate nearby farms and endanger their organic certification.
Yet studies suggest the likelihood of diamondback moths straying is low. Wild moths released into the open tend to stay put as long as they have food and company. Any that do venture farther afield are likely to be wiped out by New York’s cold winter.
Even if strays are found, legal experts say that national organic standards penalize only the deliberate use of a genetically modified organism.
“If these moths came across into an organic field inadvertently, that would not be a problem for the farmer,” said Susan Schneider, a professor who specializes in agriculture and food law at the University of Arkansas School of Law.
Insects that do wander into other fields can be identified by their red glow under ultraviolet light — caused by another gene inserted into their DNA, this one from coral.
Even if the moths in Dr. Shelton’s experiments pass muster, there is still no guarantee that farmers will use them.
“At the end of the day, the technology may not go forward for commercial reasons,” said Mark Benedict, an entomologist at the Centers for Disease Control and Prevention.
Other weapons developed for combating diamondbacks — larva-eating wasps, for instance — have struggled to compete with cheap chemical pesticides.
“What almost always happens is the pesticides take precedent,” said Michael Furlong, an entomologist at the University of Queensland. “The growers can’t resist spraying, as it’s the easiest thing to do.”
As for Mr. Hansen, he says he has not ruled out using the genetically engineered moths one day in the continuing battle to save his cabbages.
“I’m glad they’re doing these experiments,” he said. “But it’s really early days.”
They tried to charge me $200 per ticket more than the price listed. That is $600!!!! for 3 tickets for a flight from Hartford to Charlotte. The website had me enter all personal information, seat assignments and credit card info. I hit enter to confirm the flights and it just went back to the home page, with no booking info, error message or confirmation. I had to call Orbitz to find out the status of my booking, was placed on hold for 20 minutes before they hung up on me. I had to call back and they told me the price went up and they would rebook me for $200 per ticket. I don't own stock in Orbitz, but with this kind of customer service, why would you?
Baxalta’s Cambridge-based R&D chief describes new model as ‘small R, big D’
Aug 20, 2015, 12:12pm EDT
Since Baxalta rejected a $30 billion bid from Shire last month, Baxalta CEO Ludwig Hantson has called the company’s pipeline of potential drugs “underappreciated” and said that “the new research and development model is gaining positive momentum.”
But while the efforts by Shire (Nasdaq: SHPG) to acquire the newly spun-out Baxalta (NYSE: BXLT) have so far been unsuccessful, they have succeeded in focusing a lot of attention on the R&D efforts at the new company, which are mostly centered around its new Kendall Square facility. About 220 of the 500 employees the company anticipates working there by the end of this year are already on site. The facility is still under construction, but that didn’t stop John Orloff, Baxalta’s head of R&D, from taking a few minutes to sit down with me in one of the side offices on-site earlier this week and give some specifics on the “new R&D model” touted by Hantson.
The first surprise on my first visit to the new 200,000-square-foot facility is that there is no laboratory space planned. How can you have an R&D headquarters without lab space? Turns out, the idea that the Cambridge facility is purely an R&D center is “a little bit of a misnomer,” said Orloff.
“We’re kind of a ‘small “R”, big “D”,’ said Orloff, a Maine native who spend much of the past 20 years overseeing clinical trial efforts at Merck & Co. and Novartis. “Our whole approach is one based on external innovation.”
In essence, Orloff’s vision for the future of Baxalta’s drugs is one that depends heavily on discovery and pre-clinical research done at the university level and at small biotechs. With existing partnerships already in place with local companies like Momenta Pharmaceuticals (Nasdaq: MNTA) and Merrimack Pharmaceuticals (Nasdaq: MACK), Orloff says the biggest reason that Baxter International (NYSE: BAX) was so intent on finding a space in Kendall Square was to “rub elbows” with scientists and executives from smaller companies, with the hope of finding promising early-stage drugs it can partner, in-license or acquire.
from 1,608,362 to 2,162,698 shares. Vanguard Extended Market Index Funds increased ZIOP holdings from 1,117,339 to 1,303,513 shares per filings today.
in MIT Review - When Milton Wright III got his third cancer diagnosis, he cried until he laughed. He was 20 and had survived leukemia twice before, first when he was eight and again as a teen. Each time he’d suffered through years of punishing chemotherapy.
But now he had checked himself in to Seattle Children’s Hospital. An aspiring model, he had taken a fall before a photo shoot and found he couldn’t shake off the pain in his ribs. When the doctors started preparing him for a spinal tap, he knew the cancer was back. “I said, Oh, man, they are going to tell me I relapsed again,” he recalls. “They’re going to give me my six months.”
The third time wasn’t good, he knew. He’d seen enough sick kids at the Ronald McDonald House to know that when leukemia comes back like this, it’s usually resistant to chemotherapy. Hardly anyone survives.
But Wright did. In 2013 his cancer, acute lymphoblastic leukemia, was destroyed with a new type of treatment in which cells from his immune system, called T cells, were removed from his blood, genetically engineered to target his cancer, and then dripped back into his veins. Although Wright was only the second person at Seattle Children’s to receive the treatment, earlier results in Philadelphia and New York had been close to miraculous. In 90 percent of patients with acute lymphoblastic leukemia that has returned and resists regular drugs, the cancer goes away. The chance of achieving remission in these circumstances is usually less than 10 percent.
Those results explain why a company called Juno Therapeutics raised $304 million when it went public in December, 16 months after its founding. In a coup of good timing, the venture capitalists and advisors who established Juno by licensing experimental T-cell treatments in development at Seattle Children’s, the Fred Hutchinson Cancer Research Center, and hospitals in New York and Memphis took the potential cancer cure public amid a historic bull market for biotech and for immunotherapy in particular. Its IPO was among the largest stock market offerings in the history of the biotechnology industry.
The T-cell therapies are the most radical of several new approaches that recruit the immune system to attack cancers. An old idea that once looked like a dead end, immunotherapy has roared back with stunning results in the last four years. Newly marketed drugs called checkpoint inhibitors are curing a small percentage of skin and lung cancers, once hopeless cases. More than 60,000 people have been treated with these drugs, which are sold by Merck and Bristol-Myers Squibb. The treatments work by removing molecular brakes that normally keep the body’s T cells from seeing cancer as an enemy, and they have helped demonstrate that the immune system is capable of destroying cancer. Juno’s technology for engineering the DNA of T cells to guide their activity is at an earlier, more experimental stage. At the time of its IPO, Juno offered data on just 61 patients with leukemia or lymphoma.
Juno is located in South Lake Union, a Seattle neighborhood dominated by Amazon.com, whose CEO, Jeff Bezos, was an early investor in the company. During a day spent at Juno’s labs and offices in May, the phrase I heard repeated over and over was “proof of principle.” That’s what cases like Wright’s have provided. The studies are small, with no control groups, no comparisons, but also no other explanation than T cells for why the cancer disappears. “It’s proved that the T cell is the drug,” says Hans Bishop, a former Bayer executive who is the company’s CEO.
Bishop argues that medicine is entering a new phase in which cells will become living drugs. It is a third pillar of medicine. The pharmaceuticals that arose from synthetic chemistry made up the first pillar. Then, after Genentech produced insulin in a bacterium in 1978, came the revolution of protein drugs. Now companies like Juno are hoping to use our own cells as the treatment. In the case of T cells, the tantalizing evidence is that some cancers could be treated with few side effects other than a powerful fever.
Medicine is entering a new phase in which cells will become living drugs.
Moving beyond the proof of principle won’t be easy. No one has ever manufactured a cellular treatment of any commercial consequence. It’s not certain what the best way to make and deliver such personalized treatments would be. Nor is it clear whether engineered T cells can treat a wide variety of cancers; this year Juno and others are launching new studies to find out. Even in leukemia, cancer that affects the bone marrow and blood, it’s too early to declare a cure. The majority of patients receiving the therapy have been treated only in the last 12 months. About 25 percent have seen their cancers roar back, sometimes mutated in a way that makes them immune to the T cells. At 18 months since his treatment, Wright, who hopes to become a police officer, is one of the longest survivors.
Juno isn’t the only company chasing the T-cell idea. More than 30 companies have started clinical tests or are planning them, including Novartis, which says it may file for approval for a competing leukemia treatment in 2016. The U.S. Food and Drug Administration last summer gave both Novartis and Juno so-called breakthrough designation, meaning that their leukemia treatments could be approved after only one larger clinical trial.
If early results hold, tests of engineered T cells in blood cancers may lead to one of the fastest approvals in the history of drug development. It could take as little as seven years, whereas the average drug takes closer to 14 years. “That is unheard of in the industry,” says Usman Azam, head of gene and cell therapy for Novartis.
At Juno I met the CFO, Steven Harr, who before joining the company was an investment banker specializing in biotech at Morgan Stanley. I asked whether he’d ever paid attention to cell therapy companies while on Wall Street. No, he said. Just the opposite. They were considered dogs, chasing an idea that didn’t work—and even if it did, it was too complicated to commercialize. The FDA lists 14 approved cell therapies, most of which are skin grafts or involve storing umbilical cords.
But Harr says he “jumped on the bandwagon” when he saw the data from the leukemia patients. Now he thinks Juno will find an economic advantage by solving the difficult problem of how to commercialize cellular treatments. “It’s a living thing—it’s different from a pill,” he says.
“They hyped it up, like it was going to be amazing,” Wright remembers. He’d signed up for the clinical trial right away, but he didn’t tell anyone he was at the hospital. His mom was texting him: “Where you at? What’s up?” After a few days he finally told her. “I’m at Children’s. I’m getting ready for a trial.” Wright underwent a two-hour process known as leukapheresis, in which his blood was passed through a device to separate out the T cells. The cells were taken to a lab, where a strand of new DNA was inserted using a virus. Two weeks later he got the treatment: a 10-minute drip from an IV bag to reinfuse the cells. Easy stuff compared with chemotherapy. And at first, nothing happened.
A sign of how potent the T-cell treatments are is that most patients suffer from “cytokine release syndrome,” a storm of molecules generated as the cells fight the cancer. At least seven patients have been killed by the syndrome. Wright’s doctors kept checking in to see if he had developed a fever, which would signal that the T cells were working. “They were pressuring me—‘Come on, call us,’” he says. Two weeks later it came on like a body-flattening flu. He was admitted to the ICU and says he was barely lucid when smiling doctors told him they couldn’t find cancer in his body.
Carl June, the University of Pennsylvania doctor who publicized some of the first successful treatments with engineered T cells, has likened what’s happening inside patients’ bodies to “serial killing” and “mass murder.” As the billions of T cells in a dose multiply, they can locate and kill several pounds of tumor.
That’s something normal T cells don’t do. One reason is that they’re trained not to harm your body, an effect known as tolerance. The training occurs in the thymus, the organ for which T cells are named. Each cell bristles with thousands of copies of a single receptor, its shape generated at random by shuffled DNA (a quintillion possible arrangements are possible). T cells whose receptor attaches strongly to surface markers, called antigens, on the body’s own cells are discarded. The rest head out to patrol for foreign-looking viruses, bacteria, or infected cells, which they stick to and destroy. “The problem is that cancer is you,” says Michel Sadelain, a researcher at Memorial Sloan Kettering Cancer Center and one of Juno’s scientific founders. “The antigens on cancer just aren’t that enormous and juicy.”
Credit for the idea of getting around tolerance with an engineered T cell goes to an Israeli scientist named Zelig Eshhar. In a study published in 1989 in the Proceedings of the National Academy of Sciences, he replaced the T cell’s natural receptor with one that he chose. Eshhar realized that with his technique, a T cell could be engineered to attach to whatever it was instructed to attach to.
It’s an idea as dangerous as it is powerful. The reason is that few antigens appear exclusively in cancer cells. In 2009, a woman given T cells engineered to recognize colon cancer suddenly went into respiratory distress; she died five days later. Doctors at the National Cancer Institute quickly canceled the study, concluding that the T cells had encountered their antigen in her lungs and attacked.
Scientists like Sadelain soon zeroed in on one ideal antigen, called CD19. It appears nowhere in the body except on B cells, the same kind that go awry in lymphoma and in the leukemia that afflicted Wright. And it turns out that wiping out a person’s B cells isn’t life-threatening. With shots of immunoglobulin, you can live without any for years.
By 2010, doctors at Memorial Sloan Kettering, Penn, and the National Cancer Institute had begun trying to treat leukemia patients with T cells bearing a doctored receptor for CD19. To the inside of the receptor, they’d added another snippet of DNA that stimulates the cells to divide. No one is sure how the stimulation works, but without it, the modified T cells don’t do much. Early case reports eventually multiplied into trials that have treated about 350 leukemia and lymphoma patients. The results are remarkable, partly because they’re so consistent, even though each lab uses slightly different DNA designs.
Penn’s first results were well publicized and drew the attention of Novartis, the world’s second-largest drug company. In August 2012, it agreed to give the university $20 million to build a new cell-therapy center as part of an alliance through which Penn’s T-cell therapies will be sponsored and owned by the Swiss pharmaceutical giant. The deal was notable for being struck on the basis of published data from just three patients, and now it looks like a bargain.
It also makes Juno a “fast follower,” in startup parlance. Incorporated in August 2013, it is “a company of many fathers,” says Lawrence Corey, an infectious-disease doctor who was then the president of Fred Hutchinson. Corey, aided by the venture capitalist Bob Nelsen and Richard Klausner, the former director of the National Cancer Institute and now chief medical officer of the DNA-sequencing company Illumina, created Juno by buying up patents and licensing rights to T-cell trials under way in Seattle and at Sloan Kettering in New York.
It’s an idea as dangerous as it is powerful. At least seven patients have been killed.
Since its IPO, Juno’s stock market value has surged above $6 billion, reflecting intense speculation that engineered T cells will prove to be a new way to treat many types of cancer, not only the relatively rare leukemia Wright suffered from. Juno’s executives believe that they can quickly come up with new T cell designs and obtain a “fast readout” by testing them in terminal cancer patients, where risks are easy to justify. The company plans to have 10 studies of six different T-cell designs in progress by next year. “We are looking for breakthroughs,” says Mark Frohlich, a doctor who is Juno’s vice president for strategy. “We aren’t going to say, ‘Okay, two months survival.’”
Michel Sadelain, shown here at Memorial Sloan Kettering, helped carry out one of the first clinical trials of T cells in leukemia patients.
The big question mark is whether T cells will work in cancers other than those of the blood. The week before I visited Juno, investors briefly sent its shares tumbling by 35 percent after Novartis and Penn reported that low doses of engineered T cells had no dramatic effects in five patients with cancers of the pancreas, ovaries, or lung. Still, the data were too preliminary to indicate much. “We know it’s feasible. But how many cancers can you apply this to? That we don’t know,” says Sadelain. “What’s changed is that everyone now knows what to do. I think that partly explains the frenzy around T cells.”
The goal is to find the next CD19. But that’s not easily done. Since few antigens appear only on tumor cells, any targeted T cell runs the risk of wiping out vital organs, as happened to the colon cancer patient in 2009. The Recombinant DNA Advisory Committee, a federal body that oversees gene therapy, called a meeting this June to debate how scientists planned to avoid these and other side effects. One way to lessen the risk is already being tested in patients: “suicide switches,” which let doctors rapidly kill off all the engineered T cells should any serious problems arise. This spring, Michael Jensen, a pediatric cancer doctor at Seattle Children’s whose cell-therapy center treated Wright, opened a study to treat neuroblastoma, the most common cancer affecting infants. He says T cells will target an antigen found on nerve cells. If the T cells do unexpected damage, they can be inactivated with a dose of the drug Erbitux.
Safety isn’t the only obstacle. How can engineered T cells be made to persist in a person’s body to provide permanent protection? So far they don’t seem to linger in many patients, something Frohlich terms a “big problem.” And dense organ tumors can saturate their surroundings with signals, like a molecule called PD-L1, that turn T cells off. This defense is the process that checkpoint inhibitors, the new immunotherapy drugs sold by Merck and Bristol-Myers Squibb, interfere with. But DNA engineering may offer clever solutions as well. Jensen says he rewired the DNA of T cells so this “off” signal instead provokes them to kill even more.
Jensen is optimistic that rapidly improving techniques for modifying genes, and for handling and growing cells, will let researchers conquer solid tumors. “What is in the clinic now with leukemia is version 1.1 of this operating system,” he says. “But back in the labs, that is already antiquated technology.”
Given that it took 20 years to come up with the results in leukemia, Sadelain told me, “it would be naïve to expect a breakthrough every quarter.” Yet a dozen newly launched studies on T cells mean some big results could be in the wings.
One study I heard about is led by Marcela Maus, an oncologist at Penn, who this year tested engineered T cells in five patients with glioblastoma, an incurable brain cancer. When one of these patients underwent brain surgery, Maus discovered that the tumor had been mostly killed. No cancer cells with the marker she’d aimed at remained at all. So was this proof that T cells can treat brain cancer, too? Maus is reluctant to answer that question. “Potentially,” she says. It’s just too soon to know if these patients will live any longer than they would have otherwise. “It’s hard to exercise patience, but that is what is needed,” she says.
When Wright’s white blood cells were collected in late 2013, they headed to a processing facility at Seattle Children’s. Workers laboring in masks and safety suits placed them into bioreactors and used a virus to insert the new DNA. Then the cells were grown for 10 days inside plastic sacks fed with human blood serum. If a half-dozen academic centers hadn’t built specialized clean rooms like this one, there wouldn’t be any clinical trials, or any IPOs. But Jensen’s center is no commercial operation: it can prepare cells for only 10 patients a month. It costs $75,000 to manufacture cells for each one.
Jensen says about a quarter of the children whose parents want to enter them in the Seattle study aren’t accepted. Sometimes the reasons are medical, but not always: capacity is simply limited. “I wish every kid could get it,” Jensen says of the cell treatment. “The major barrier is the commercial end of it—having their factories built, having their trials done, and it being something that a doctor would be able to write a prescription for in any part of country.”
In fact, no one is quite sure how a personalized cell therapy will be commercialized at a large scale. Schematics outlining how it would work typically show not just a dozen complex laboratory steps but two airplanes, to get cells to and from patients. That explains why the largest number of Juno’s employees are involved in process engineering. One of them, Chris Ramsborg, gave me a tour around what he called the “sandbox” where new ideas for growing and packaging cells are being worked out. But most of the equipment was hidden from sight. “The manufacturing technology and how we are deploying it is the secret of Juno,” he said. “The techniques to make these products don’t really exist yet.”
Several members of Juno’s staff, including Ramsborg, Frohlich, and Hans Bishop, worked at another Seattle biotech named Dendreon, which developed a T-cell treatment for prostate cancer. (The cells, instead of being engineered, were exposed to cancer antigens and then multiplied. The treatment was only modestly effective.) Even though Dendreon charged $93,000 for its treatment, it cost half that much to manufacture. The company filed for bankruptcy last year.
Dendreon’s manufacturing plant in New Jersey was scooped up by Novartis, which has started using it to process cells for patients involved in its leukemia study. Azam says Novartis, which has 400 people working in gene and cell therapy, is already studying the logistics of how a personalized cell therapy could be offered globally. “We have been mapping out how we would do the patient journey, the individual cell journey,” he says. “It’s a new way to treat patients, but also a new way of practicing business.”
It may one day be possible to mass-produce off-the-shelf T cells or even do genetic engineering at a patient’s bedside. Some labs are working with instruments to pump genetic material into cells using electricity or pressure. Others have shown they can generate T cells in a lab dish and use them to cure mice, raising the possibility of T-cell factories. For now, though, all the engineered T-cell treatments in clinical testing use a patient’s own cells.
So how much will a dose of genetically engineered immune cells cost? One Citigroup analyst estimated that the price could exceed $500,000. That would be more expensive than nearly any existing cancer drug. Yet it might be considered cheap if a 10-minute drip could effectively treat leukemia without causing permanent damage to the patient. Current chemotherapy treatments last for a year or more and can weaken a person’s heart and body for a lifetime. The hospital bills for leukemia patients can top $2 million.
Harr, Juno’s CFO, was well known on Wall Street for criticizing the high cost of cancer drugs; he warned that the government might step in and set prices if they weren’t reined in. When I asked him about the T-cell treatments, he said it was too soon to guess at a price. It depends how well they work and how hard they are to make. “There’s no model for how much it costs,” he said. “But remember, we get to utter words like ‘cure.’ And at this point, it’s a single dose.”
Immunotherapy. 2015 Aug 27. [Epub ahead of print]
Strategies for combining immunotherapy with radiation for anticancer therapy.
Seyedin SN1, Schoenhals JE2, Lee DA3, Cortez MA2, Wang X2, Niknam S2, Tang C1, Hong DS4, Naing A4, Sharma P5, Allison JP5, Chang JY1, Gomez DR1, Heymach JV6, Komaki RU1, Cooper LJ7, Welsh JW1.
Radiation therapy controls local disease but also prompts the release of tumor-associated antigens and stress-related danger signals that primes T cells to promote tumor regression at unirradiated sites known as the abscopal effect. This may be enhanced by blocking inhibitory immune signals that modulate immune activity through a variety of mechanisms. Indeed, abscopal responses have occurred in patients with lung cancer or melanoma when given anti-CTLA4 antibody and radiation. Other approaches involve expanding and reinfusing T or NK cells or engineered T cells to express receptors that target specific tumor peptides. These approaches may be useful for immunocompromised patients receiving radiation. Preclinical and clinical studies are testing both immune checkpoint-based strategies and adoptive immunotherapies with radiation.
CHIMERIC ANTIGEN RECEPTORS AND METHODS OF MAKING Document Type and Number:
WIPO Patent Application WO/2015/123642
Provided are methods of generating chimeric antigen receptors (CAR). In some embodiments, library screening of CAR is performed by generating a vector encoding the CAR from random attachment of vectors from libraries of vectors encoding antigen-binding domains (e.g., scFv regions), hinge regions, and endodomains. In some embodiments, the vectors contain a transposon.
COOPER, Laurence, J.N. (311 West 8th St, Houston, TX, 77007, US)
KORNGOLD, Ana, Beatriz (402 Tuam St, Unit 9Houston, TX, 77006, US)
RABINOVICH, Brian, A. (3815 Latma Dr, Houston, TX, 77025, US)
SINGH, Harjeet (9851 Meadowglen Lane, No.52Houston, TX, 77042, US)
OLIVARES, Simon (2825 Bellefontaine St, Apt. 247, Houston TX, 77025, US)
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BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM (201 West 7th St, Austin, TX, 78701, US)
C12N15/85; C07K14/705; C07K19/00
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FINDLAY, Geoffrey, S. (Parker Highlander PLLC, 1120 S. Capital Of Texas HighwayBuilding One, Suite 20, Austin TX, 78746, US)
Sleeping Beauty is not just for cancer treatment
Ron DePinho, President of MD Anderson told me, "We have a confluence of major discoveries and technologies that have occurred across a wide range of fronts, which allow us to understand life and disease at a basic level and use those insights to influence its processes. We are now able to make a decisive assault on the cancer problem, if we have the resources."
From German study -
Generation of human induced pluripotent stem cells using the
Sleeping Beauty transposon system
As the first one reconstructed DNA transposon, the Sleeping Beauty transposon is the
most thoroughly studied vertebrate transposon to date, and it has shown efficient
transposition in mammalian cells. The Sleeping Beauty transposon system is composed of a transposase source and a transposon vector flanked by inverted terminal repeats (ITRs). In the presence of the transposase, the transposon is mobilized by the “cut and paste” transposition. During the transposition reaction, the transposon is excised and then gets reintegrated into a different locus in the genome. The Sleeping Beauty transposon system can be used as a non-viral gene delivery tool, and thereby opens up new possibilities for genetic manipulation in cells, animal models as well as for human gene therapy.
Compared with the viral vectors currently in use, the Sleeping Beauty transposon has
many favorable advantages as a gene delivery system, including its reduced
immunogenicity, relaxed limitation on the size of expression cassettes, and improved safety/toxicity profiles. In comparison to the PiggyBac transposon whose
integration features resemble retroviral vectors, the Sleeping Beauty transposon integration occurs fairly randomly in the genome. In addition, by means of SB100X, a novel hyperactive transposase developed in our lab, the Sleeping Beauty transposon shows robust transposition activity. Furthermore, the Sleeping Beauty transposon seems to trigger significantly milder epigenetic changes at the genomic insertion sites. More importantly,
the Sleeping Beauty transposon is capable of supporting stable, long-term transgene
expression both in vitro and in vivo with lower transgene silencing than viral vectors.
As described in the “Introduction” part, the reprogramming efficiency of somatic cells,
especially in human, using non-integrative methods is quite low, while the integrated
approaches like viral vectors and the PiggyBac transposon may raise the safety concerns
by disrupting endogenous genes (e.g. reactivating oncogenes or repressing tumor repressors) in iPSCs. Given the advantages of the Sleeping Beauty transposon, I tried to
establish an alternative approach for reprogramming both mouse and human fibroblasts
into iPSCs, based on the Sleeping Beauty transposon system. Importantly, when
compared to the PiggyBac transposon, Sleeping Beauty-transfected cells exhibit fewer
numbers of integrants per cell, and it is easier to derive single-copy integrants. The Cre-loxP system is integrated into the Sleeping Beauty transposon system, in order to exchange the Yamanaka factors with the genes of interest. Using this combined method, it is expected that the monogenetic patient-derive iPSCs can be corrected with the therapeutic gene meanwhile the Yamanaka factors can be removed. Additionally, this Sleeping Beauty-based reprogramming method can be used to generate transgenic animals from “single-copy-insertion” iPSCs.
Dr Cooper collaborated with them on pancreatic cancer.
MP2. Single-Cell TCR Sequencing from Pancreatic Cancer TIL
Amir Alpert1, Hiroki Torikai2, Lawrence Cooper1,2
1. UT Houston Graduate School of Biomedical Science, Houston, TX, 77054 2. Pediatrics, MD Anderson Cancer Center, Houston, TX, 77054
Patients with pancreatic cancer face a grim prognosis. Surgical removal is the only option that leads to long term survival; however, this option is only available for a small percentage of patients. Pancreatic tumors contain a large number of tumor infiltrating lymphocytes (TIL), indicating that T-cells recognize pancreatic tumor antigens. In collaboration with a private biotech company (Immatics), we have begun a new initiative to create immunotherapy based treatments for patients with pancreatic cancer. We will perform single-cell T-cell receptor sequencing from TIL found in pancreatic cancer biopsies. These sequences will then be used to create a pancreatic specific T-cell receptor library. We will then screen this library for the ability to recognize MHC restricted peptides that are overexpressed in pancreatic cancer. By the end of this project, we aim to identify pancreatic tumor specific TCRs and their cognizant tumor associated antigens, which may eventually be used in adoptively transferred T-cell therapeutics.
at Children's Hospital in Alabama October 22nd, 2015
12:00-1:00 KEYNOTE ADDRESS
The Moral Imperative to Implement New
Therapies for Childhood Cancer:
How T cells Can Be Infused as a Drug
Laurence Cooper, MD, PhD
Thursday, 8 October 2015
Session 3 – Tools For Genome Engineering
Engineering the genome with transposons
Zoltan Ivics, Head of Division, Paul Ehrlich Institute, Germany
Structure-based engineering for the advancement of transposon tools: the case of Sleeping Beauty
Orsolya Barabas, Group leader, EMBL Heidelberg, Germany
Diamondback Moth Project
Posted on Monday, August 24, 2015
Tony Shelton, professor of entomology at Cornell University, and Neil Morrison, scientist at Oxitec Ltd, will share the results of their groundbreaking Diamondback Moth (DBM) Project research in a talk titled, "Safe Sex for Insects: New Technologies for Pest Control," on Wednesday, Sept. 23, at 7 p.m. in Albright Auditorium. The DBM project is a scientific evaluation of a way to manage local pest populations of DBM moths by introducing a genetically engineered DBM into the population.
"Effective control of insect pests is critical in agriculture and many farmers are looking for ways to reduce their use of pesticides," says Professor of Biology Beth Newell, who helped coordinate the event sponsored by the Biology Department. "Pesticides - whether synthetic or organic, sprayed on or produced within the plant - are toxins. If this technology works, it could reduce the use of pesticides on crops like cabbage, cauliflower, broccoli, and kale."
After successful completion of laboratory and greenhouse studies in the UK and at Cornell University, Shelton furthered the evaluation of the genetically engineered moths by conducting field cage trials at Cornell's Agricultural Experiment Station in Geneva this summer.
The DBM is the world's worst insect pest of brassica crops, like cabbages, canola, broccoli, cauliflower and kale. Female DBMs can lay up to 150 eggs in their lifetime, creating entire generations of the moth that continue to wipe out crops across the country and around the world.
To mitigate the damage, the British biotech company, Oxitec, developed the pest control method of genetically engineering a strain of DBM with a "self-limiting gene" that prevents female offspring from developing. Unlike insecticides, which can harm beneficial insects and other non-target organisms, using Oxitec DBM would only control this one invasive species.
"The goal of this technology is to use genetically engineered diamondback moths to suppress moth populations in fields where these crops are grown," explains Newell. "We live in a region of some of the best farmland in the country; agriculture is the mainstay of the economy in the Finger Lakes region. Given this, we should all be interested in learning about factors that influence the environmental and economic sustainability of agricultural ecosystems."
This summer, Shelton conducted a trial in which cabbages, DBMs and GE moths were introduced into field cages. The trial assessed four objectives: the mating competitiveness in male genetically engineered moths, the longevity of male genetically engineered moths, the reproductive rate of pest moths, and the suppressive effect of male genetically engineered moths on the pest DBM.
Shelton and Morrison will discuss the results of the trial and the implications this has for the future of pest control, as well as the reasons for some of the backlash the project is receiving from critics. Concerned about the potential for GE contamination in crops, some critics are opposed to outdoor trials. Shelton says that until further evaluation is conducted, conclusions cannot be drawn about the effectiveness and potential threats of using GE insects as a pest control method.
"Some people are categorically opposed to genetic engineering of living organisms, and others disagree about whether the benefits outweigh the costs," Newell explains. "I hope everyone will come to this talk with an open mind. We'll have an opportunity to learn about the science behind this technology as well as discuss its pros and cons. Crop losses to insect pests are costly to farmers everywhere, and we want to know if this could technology could help and prevent some of those losses."
10:30 Engineering T Cells for One and All
Harjeet Singh, Ph.D., Research Investigator, Pediatrics, MD Anderson Cancer Center
The administration of genetically modified T cells is championed by academia and industry alike. T cells are precision tools and one challenge now is to render them suitable for broad appeal as immunology is translated into immunotherapy. To help democratize T-cell therapy, I will reveal strategies how immune cells can be engineered ex vivo using a transposon/transposase system for in vivo applications. I will discuss how this non-viral approach to gene therapy can be combined immunotherapy to redirect specificity and improve the effector functions of T cells manufactured for clinical trials. For example, T cells can be genetically modified to express chimeric antigen receptors (CARs) to redirect specificity for cell-surface tumor-associated protein antigens and carbohydrates on fungi. I will reveal how the Sleeping Beauty (SB) system can be adapted and used to stably express CARs and TCRs to improve the therapeutic potential of clinical grade T cells. These clinical data serve as a foundation for additional genetic engineering to co-express transgenes to improve persistence as well as provide the opportunity for genome editing to eliminate undesired endogenous genes to improve T-cell potency and broaden their distribution and application.
The market selloff has "definitely" provided a buying opportunity, legendary investor Bill Miller said Monday.
"What happened Friday and at the open today was that the froth was blown off the beer. It's better without the froth," the chairman of LMM told CNBC's "Closing Bell" on Monday.
Whipsaw action in the stock market saw the Dow Jones industrial average plunge more than 1,000 points at the open Monday and then climb back up and drop again. The index was last down nearly 500 points.
Miller is specifically buying the homebuilders, and airlines, as he thinks that sector could "easily" be up 25 percent in the next 12 months. He is also buying the big banks, some tech, like Apple, and biotech names such as Intrexon and Ziopharm.