Genetically modified fruit flies could be future of Medfly control
West Australian researchers are hoping a genetically modified fruit fly will help break the breeding cycle of the Mediterranean fruit fly, a destructive pest.
Mediterranean fruit fly, or Medfly, is a significant horticultural pest that causes an estimated $200 million damage to West Australian crops each year.
The Department of Agriculture and Food Western Australia (DAFWA) is looking at alternative methods of Medfly control after the phasing out of insecticide fenthion.
DAFWA has now teamed up with UK technology company Oxitec to trial the effectiveness of a new method of Medfly control using genetically modified organisms (GMO).
Oxitec research group leader Neil Morrison said the method worked a bit like Medfly sterilisation, which is another method of pest control.
Mr Morrison said a "self-limiting gene" is inserted into male fruit flies, which prevents the female offspring from reaching adulthood.
A fly on a leaf.
PHOTO: Mediterranean fruit fly is a destructive horticultural pest in Western Australia. (Supplied: Department of Agriculture and Food, Western Australia.)
"If you reduce the number of females, that knocks down the pest population in the next generation," he said.
Mr Morrison said his company had used the genetic modification technique to reduce numbers of dengue fever mosquitoes, Aedes aegypti, in Brazil, Panama and the Caribbean.
He said the Aedes aegypti trials had resulted in population suppression of more than 90 per cent.
"That's a level way beyond what conventional approaches can achieve," he said.
Mr Morrison said the GMO option was appealing because it did not rely on "chemicals or toxins".
He said Oxitec had conducted feeding studies that found there were no adverse affects on predators who fed on the genetically modified pests.
Success depends on local female Medfly attraction to 'British boys'
DAFWA director of horticulture development David Windsor said the department was set to begin greenhouse trials at its South Perth facility in 2016.
Dr Windsor said the department imported the GMO fruit fly strain from Oxitec in the UK last month.
He said the next step was to breed 5,000 flies for colony testing.
"What those test are essentially about is do the local WA girls of the Medfly world like the British boys," he said.
"The first question we have to answer in terms of if this is going to be an effective technique is, are the flies compatible with each other."
Dr Windsor said the first test for the trial would be to put Oxitec male flies alongside Medfly pest flies and the local female population to observe the mating preference.
Reiterated Targeting Peptides on the Nanoparticle Surface Significantly Promote Targeted Vascular Endothelial Growth Factor Gene Delivery to Stem Cells
#$%$-#$%$ Wang?, Mingying Yang*�, Ye Zhu?, and Chuanbin Mao*?
? Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, Oklahoma 73019, United States
� Institute of Applied Bioresource Research, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang 310058, China
Publication Date (Web): November 20, 2015
Nonviral gene delivery vectors hold great promise for gene therapy due to the safety concerns with viral vectors. However, the application of nonviral vectors is hindered by their low transfection efficiency. Herein, in order to tackle this challenge, we developed a nonviral vector integrating lipids, sleeping beauty transposon system and 8-mer stem cell targeting peptides for safe and efficient gene delivery to hard-to-transfect mesenchymal stem cells (MSCs). The 8-mer MSC-targeting peptides, when synthetically reiterated in three folds and chemically presented on the surface, significantly promoted the resultant lipid-based nanoparticles (LBNs) to deliver VEGF gene into MSCs with a high transfection efficiency (?52%) and long-lasting gene expression (for longer than 170 h) when compared to nonreiterated peptides. However, the reiterated stem cell targeting peptides do not enable the highly efficient gene transfer to other control cells. This work suggests that the surface presentation of the reiterated stem cell-targeting peptides on the nonviral vectors is a promising method for improving the efficiency of cell-specific nonviral gene transfection in stem cells.
A number of different strategies have been employed to identify genes for which genetic variation contributes to type 1 diabetes (T1D) pathogenesis. Genetic studies in humans have identified 40 loci that affect the risk for developing T1D, but the underlying causative alleles are often difficult to pinpoint or have subtle biological effects. A complementary strategy to identifying "natural" alleles in the human population is to engineer "artificial" alleles within inbred mouse strains and determine their effect upon T1D incidence. We describe the use of the Sleeping Beauty (SB) transposon mutagenesis system in the nonobese diabetic (NOD) mouse strain, which harbors a genetic background predisposed to developing T1D. Mutagenesis in this system is random, but a green fluorescent protein (GFP)-polyA gene trap within the SB transposon enables early detection of mice harboring transposon-disrupted genes. The SB transposon also acts as a molecular tag to, without additional breeding, efficiently identify mutated genes and prioritize mutant mice for further characterization. We show here that the SB transposon is functional in NOD mice and can produce a null allele in a novel candidate gene that increases diabetes incidence. We propose that SB transposon mutagenesis could be used as a complementary strategy to traditional methods to help identify genes that, when disrupted, affect T1D pathogenesis.
November 20, 2015 1:49 PM EST
Griffin Securities analyst Keith Markey reiterated a Buy rating and $65 price target on Intrexon (NYSE: XON) saying it is positioned to become the General Electric of genetic engineering.
Markey commented, "GE was founded on the use of electricity for lighting initially. But it rapidly expanded into electric railroad engines through a merger and diversified into power generation and transmission and into electric motors for a variety of industries. We believe Intrexon is on a similar path based on its foundational technologies in genetic engineering. Much like electricity, this new technology can be applied to applications that are completely unrelated, except through the underlying technology’s ability to achieve a desired outcome."
Shares of Intrexon closed at $36.65 yesterday.
November 22, 2015
Adding adjuvant gene-mediated cytotoxic immunotherapy (GMCI) using aglatimagene besadenovec (AdV-tk) and valacyclovir to standard of care (SOC) improves survival among patients undergoing surgery for newly diagnosed malignant glioma—particularly among patients undergoing gross total resection, according to findings from a phase II multicenter study reported at the 20th Annual Scientific Meeting of the Society for Neuro-Oncology, held November 19-22 in San Antonio, Texas.
“GMCI can be safely combined with SOC in newly diagnosed malignant gliomas,” reported lead study author E. Antonio Chiocca, MD, PhD, surgical director at the Center for Neuro-Oncology at the Dana-Farber Cancer Institute, and chairman of Neurosurgery at Brigham and Women’s Hospital in Boston. “Survival rates compared favorably to historical reports and a matched control group. Survival outcomes were significantly improved in patients with minimal residual disease after total resection.”
“This is the first study to demonstrate a correlation between maximum debulking and a survival advantage using immunotherapy,” he noted.
GMCI generates an antitumor immune system response through local delivery of an adenoviral vector expressing the herpes simplex virus (HSV)-tk gene (AdV-tk) during surgery, followed by the orally administered antiherpetic prodrug valacyclovir.
The phase II trial assessed overall survival (OS) associated with SOC plus GMCI, compared to a matched-control group receiving only SOC. “From 2006 to 2010, 48 patients completed SOC plus GMCI and 134 patients were matched from the SOC-only cohort,” Dr. Chiocca reported. “There were no dose-limiting toxicities. Fever, fatigue, and headache were the most common GMCI-related symptoms.”
Median OS was 17.1 months for SOC plus GMCI patients and 13.5 months for the SOC-only control group, he reported (hazard ratio, 0.72 [95% confidence interval, 0.52-0.99]; P = .0417), a 27% relative improvement. “OS at 1-, 2-, and 3-years increased from 57%, 22%, and 8% to 67%, 35%, and 19%, respectively,” he reported. Improvement was mostly seen in patients that underwent gross total resection: median OS increased from 16.9 in the SOC-only group to 25 months in the SOC plus GMCI group (P = .049).
Progression-free survival saw a similar 25% relative improvement with the addition of GMCI to SOC: 8.1 vs 6.5 months (P = .010).
“These data strongly support further evaluation of GMCI for malignant gliomas,” Dr. Chiocca concluded.
Viral and Non-Viral Gene Delivery for Adoptive Cell Therapy
Peter Emtage, Ph.D., Vice President, Synthetic Immunology, Intrexon
Preclinically, the effects of Ad-RTS-mIL-12 + veledimex were studied in orthotopic glioma animal models, demonstrating veledimex crossed the blood-brain-barrier. In a standard orthotopic glioma mouse model that evaluated dexamethasone, bevacizumab, temozolamide and a PD-1 inhibitor, Ad-RTS-mIL-12 + veledimex demonstrated a dramatic dose-related increase in survival, without significant adverse events, that was superior to all other treatments.
the conference starts tomorrow
XON – Unveils the Kimono at Investor Day
XON just hosted an Investor Day in New York (11/12), with management using the forum to highlight their suite of proprietary technologies and BeyondBio informatics platform. The company emphasized that they can leverage their design-build-test-learn paradigm for bioengineering across a diverse, but unbelievably large (~$1 trillion in aggregate) set of end markets, including healthcare, food, energy, environment and consumer.
XON provided an update on Intrexon Energy Partners (IEP) and Dominion Resources as they continue to pursue commercialization of XON’s methane-to- isobutanol bioconversion facilities. While reiterating the commercial and environmental attractiveness of isobutanol as an add-in fuel (like ethanol), management stated that it expects the pilot facility to be up and running in early 2016. XON has achieved an impressive 2500x relative increase in isobutanol production since early 2014. Site selection and construction of the initial small-scale commercial plant is expected in 2016/2017, followed by larger commercial scale plants in 2018 and beyond. Management also reiterated that Dominion brings engineering and construction management expertise to the collaboration, as well as the capacity to build, own and operate facilities on a tolling basis. In our view, the methane conversion program is one of XON’s most valuable programs outside of healthcare.
XON Multiple Near-Term/2016 Catalyst Calendar
ZIOPHARM Phase 1b/2 IL-12 Breast Cancer Data Q4:15 ZIOPHARM Phase 1 IL-12 Study in GBM Data Q4:15 ZIOPHARM Up to 5 CARs Entering the Clinic in 2015 Q4:15
￼￼INCY is a BUY under 100 with a TARGET PRICE of 120
Intrexon Energy Isobutanol Pilot Scale Plant Initiated H2:15
Fibrocell Amend Recessive Dystrophic Epidermolysis Bullosa IND Q1:16 AquaBounty Potential Salmon FDA Approval 2016
Arctic Apple Commercial Revenue 2016
ViaGen Pets Launch Animal Service and Product Offerings 2016
Sun Pharma Potential Wet-AMD Clinical Development 2016
If we had one takeaway we would emphasis from XON’s analyst day, it would be the quality of the management team that RJ Kirk has assembled. One after one we heard from some of the brightest and most innovative leaders in the world. Particularly impressive are the heath care leaders with Dr. Samuel Broder former head of the NCI, Dr. Peter Emtage who led MedImmune’s I/O program, and Dr. Laurence Cooper at ZIOP and formerly MD Anderson superstar. All of these luminaries have all come together under the XON umbrella because they believe that the company has the greatest opportunity to treat both cancer and chronic disease in the world today. While the overall presentation is too large to discuss today – we will selectively detail in future Issues – we recommend subscribers take a look at the slide show
The Money Flow Index is a volume/momentum technical indicator that measures the strength of total money flowing into and out of a stock, index or futures contract. Money Flow looks at both price and volume activity. It is similar to RSI, which looks only at price.
Money Flow (MFI) is a theory that correlates a relationship between price movement and the actual amount of money flowing in or out of a stock, index or futures contract. The belief is as money goes in or out of a security a measurable, predictive and usable pattern should exist. By measuring the amount of net money movement, supply and demand trends can be qualified, and better identified as attractive or overpriced. You are, in essence, measuring whether investors are paying more or less than market price.
Money Flow analysis identifies divergences between trends in price and trends in money flow. If the price goes up, money should be flowing into it. If the price goes down, money should be flowing out. When price is trending higher, money flow should be trending higher. When price is trending down, money flow should be trending down. Bearish divergence is when price is trending higher and money flow is falling. Bullish divergence is when price is trending lower and money flow is increasing. Price usually corrects in the direction of money flow.
ON Semiconductor Corp (NASDAQ:ON) attracted $4.61 million of the net inflows, according to data provided by the Wall Street Journal. A stock can only have an uptick if enough investors step in to buy it at a given point in time. For this company, $9.48 million shares traded on an uptick (meaning buyers lifted an offer) and $4.86 million traded on downtick trades (sellers). The up/down ratio, the value of uptick trades relative to the value of downtick trades, came to 1.95. On the same day, block money flow appeared at $4.79 million with overall inflows reaching $6.07 and reported an outflow of $1.27 million. In that case, the up/down ratio was at 4.76.
After the end of last trading session, net inflow into ZIOPHARM Oncology Inc. (NASDAQ:ZIOP) amounted to 0.8 million. For this company, $8.47 million shares traded on an uptick (meaning buyers lifted an offer) and $7.67 million traded on downtick trades (sellers). That brings up/down ratio to 1.1. The amount of funds represented in a stock’s block trades was $0.98 million with an up/down ratio of 4.77. Investors have poured $1.23 million. In contrast, $0.26 million was withdrawn from funds investing in the stock during the last business day.
Investors are buying stock in Pfizer Inc. (NYSE:PFE) as its net money inflow consisted of $113.69 million shares in total. The figure was one of the biggest in the list of largest inflows. For this company, $215.79 million shares traded on an uptick (meaning buyers lifted an offer) and $102.1 million traded on downtick trades (sellers). The up/down ratio currently stands at 2.11. Turning now to the block trade desk, the company reported a net money inflow of $114.66 million. It saw total inflows worth $141.08 million and posted $26.42 million of outflows, resulting in an up/down ratio of 5.34, according to WSJ data.
Andrew Sabin, a New York-based businessman and philanthropist, committed $30 million to support cancer research at the University of Texas MD Anderson Cancer Center.
The grant, given by the Andrew Sabin Family Foundation, will initially create up to eight two-year research fellowships at $100,000 each. Further awards will be granted depending on each application.
"This transformational gift will nurture the genius and excellence of outstanding young scientists willing to push the boundaries in our quest to end cancer," said Dr. Ronald DePinho, president of MD Anderson, in a statement. "The vision of Andy Sabin and his family will have a positive, far-reaching impact for generations to come."
The program, known as the Andrew Sabin Family Fellowship Program, will focus on cancer research through fundamental science, translational and population science research.
Applications for the fellowships are currently being accepted, and the inaugural fellows will be announced at the beginning of 2016.
Sabin is a national advocate for increased cancer research funding. He's also a widely known environmentalist and conservationist.
The University of Texas MD Anderson Cancer Center is the ninth-largest Houston-area health care system, as well as the ninth fastest-growing college campus in Houston, according to HBJ research.
Late last month, the cancer center announced that it would expand its Moon Shots program to include six more types of cancer.
When originally launched in 2013, the $3 billion program focused on breast and ovarian cancer, multiple forms of leukemia, lung cancer, melanoma and prostate cancer. The new cancers targeted are B-Cell lymphoma; brain cancer; cancers caused by the human papillomavirus, or HPV; high-risk multiple myeloma; colorectal cancer; and pancreatic cancer.
Before he was wheeled into brain surgery, Matt Futer tearfully thanked his parents for a great life.
Futer, 44, wasn't likely to die on the operating table, but his fear was understandable. Ten days earlier, he had been diagnosed with a tumor, the type so nasty it kills in an average of 15 months.
Futer's cancer was a 5-inch mass, with slender tentacles extending another 4 inches, the tumor surrounding and infiltrating areas involved in speech and language.
Trying to remove it all meant that he'd likely never be able to speak again and he'd hear spoken words as gibberish, said Dr. David Baskin, Futer's Houston Methodist Hospital neurosurgeon. "He'd be trapped in his own body."
Baskin cut out about a third of the cancer during three hours in surgery. Then he tried something radical.
He injected a virus into the tumor.
Baskin worked slowly and gently for about 30 minutes more, knowing a misstep with a needle could cause hemorrhaging. At 10 sites roughly equidistant from each other, he delivered 100-microliter doses, part cold virus, part herpes DNA. He covered each area with a surgical sealant, so nothing leaked out.
The experiment involved follow-up drug treatment targeting the virus. The hope was that the process would activate the immune system, stimulating a long-term response against the cancer's intractable, rapidly growing cells. There is no such benefit from chemotherapy or radiation.
Futer was one of the first patients to receive Baskin's treatment. Nearly a decade later, such research is still a work in progress, the techniques and infectious agents varying by scientific team, but the era of viral immunotherapy has arrived.
A New York City surgeon in the late 19th century stumbled on the idea of using infections as treatment when the cancer of a "seemingly hopeless" patient disappeared after a severe bacterial infection broke out on his face. The surgeon concluded that the body's defenses were responsible and began injecting cancer patients, more than 1,000 in all, with a mixture of heat-killed bacteria. The therapy helped many, he reported, but didn't take hold. Other doctors were more interested in a new, exciting treatment - radiation.
In the 1950s and 1960s, case reports inspired a few researchers to work with viruses. They, too, reported some success, but techniques were primitive and the viruses not easily controlled. Sometimes, the therapy killed the tumor; other times, it killed the patient. And there was another new, exciting treatment grabbing attention - chemotherapy.
By the 1990s, after enthusiasm about radiation and chemotherapy had cooled, advances in bioengineering techniques revived interest in viral immunotherapy. Researchers began to painstakingly engineer viruses - herpes was the first - successfully altering their DNA to prevent the infections from usurping healthy cells, first in mice, then in humans.
But the Food and Drug Administration, which must approve "biologic" therapies, worried about the dangers of injecting living agents that cause the death of host cells if left unchecked. There's a reason many apocalyptic science-fiction works involve genetically engineered viruses gone wrong.
"It's a pretty radical idea," acknowledged Dr. Frederick Lang, an M.D. Anderson Cancer Center neurosurgeon leading such research. "You're taking a live virus and increasing its infectivity."
The first viral immunotherapy was approved 10 years ago in China, a cold virus engineered to treat head and neck cancer. China became a mecca for those who couldn't get the therapy in their home countries.
After years of U.S. research established the therapy was safe, the FDA became sold. Late last month, it approved the first U.S. viral immunotherapy, a herpes-based biologic to treat melanoma. The benefits seem modest - in its last clinical trial, it shrank tumors in patients with advanced disease, though the survival figures stopped short of statistical significance - but researchers called it "a huge milestone."
"This is going to float all boats," said Dr. Stephen Russell, a professor of molecular medicine and viral immunotherapy researcher at the Mayo Clinic in Minnesota. "It's a signal to pharmaceutical companies that such drugs can be approved."
The treatment is known as oncolytic virotherapy, in which the virus infects and replicates inside cancer cells, causing them to burst. The eruption releases tumor proteins that prod the immune response.
Baskin's work is a cousin of such therapy. Instead of killing the tumor, his genetically engineered virus acts as a Trojan horse.
Futer, a former mechanic who managed his family's trust, first sought medical care on Christmas Eve 2006. He'd spent three days in bed, sure "something wasn't right," though all he really felt was a severe headache. By the time he got to a clinic near his Cypress home, he was vomiting profusely, a little blood mixed in. Staffers sent him to the emergency department of Methodist's Willowbrook campus.
After immediate care and testing, Futer was filling out paperwork when a doctor told him it could wait.
"That's it," he remembers the doctor saying. "Half your brain is cancer."
The left half harbored glioblastoma multiforme, the most common and most aggressive malignant primary brain tumor. Half of people diagnosed with the tumor die within a year, 85 percent within three years. Even when a surgeon seems to have removed the entire tumor, cells remain seeded in the brain, inevitably giving birth to new tumors. Doctors compare the cancer to a weed that keeps sprouting tendrils.
Willowbrook doctors sent Futer to Methodist's flagship hospital in the Texas Medical Center, where Baskin was on call. One look at Futer's scans told Baskin all he needed to know.
Baskin, 63, had always been fascinated by the mind. He aspired to be, first, a psychologist, then a psychiatrist and finally a neurologist, each time finding the newly chosen specialty an upgrade over the old one. He had no interest in surgery - "too bloody, gory" - but figured since he'd be referring patients to neurosurgeons, he should learn what they do. At a rotation soon after, an eminent neurosurgeon enlisted his assistance for a nine-hour operation removing a tumor from a patient's spinal cord.
"The next day, the patient walked," Baskin said. "I knew that's what I wanted to do."
Glioblastomas promise no such happy ending. Baskin describes the horrific moment when a patient, unaware what's ahead, looks at him and says, "What do you think, doctor?" and the answer, however delicately put, is that his disease is usually a death sentence.
The news overwhelmed Futer, who'd been happily living day to day. He was calm, stoic, but Baskin could see the fear in his eyes.
Viral immunotherapy represented a long shot, but Baskin was excited to have something to offer Futer besides standard therapy, so unlikely to make any meaningful difference. Futer was all for it, not just on the chance it might help him, but for the more likely benefit it might provide future patients.
Ten days later, Baskin performed the surgery and injected the viral drug, called AdV-Tk. When he closed up Futer's skull, he had no idea what to expect.
Many of the first researchers working with oncolytic viruses weren't counting on an immune response. They just saw a virus's potential as a killing machine.
At M.D. Anderson, for instance, the husband-wife team of Juan Fueyo and Candelaria Gomez-Manzano 15 years ago engineered a cold virus that targets proteins that exist only in cancer. Injected into brain tumors through a hole in the skull, the virus enters malignant cells and begins making copies of itself until the cells explode, which propels viral particles forward in a wave-like motion that infects other cancer cells.
Those experiments were in mice lacking immune systems. Only in a recently completed early-stage clinical trial did Lang's team confirm the therapy also generates a response from the immune system, which, tricked into thinking the patient is suffering from the common cold, mounts an attack on the virus. Cancer cells get caught in the crossfire.
Baskin's work always aimed to enlist the immune system. It dates to laboratory work, initially focused on prostate cancer, conducted at Baylor College of Medicine in the late 1990s. Intrigued by presentations of the research, Baskin determined to apply it to brain cancer, where there had been little progress over the decades.
In Baskin's research program, a non-replicating, gutted cold virus is used strategically - like the ancient Trojans with their wooden horse - to carry a piece of herpes DNA into tumor cells. The virus doesn't attack by itself, but following the injections, patients are given Valtrex, the oral medication used to treat herpes. When the drug attacks the herpes DNA, it creates a new protein that blasts the cancer cells, making them self-destruct and release other proteins that initiate an immune response.
Cold and herpes viruses are the most common infections being used as immunotherapies against cancer, but researchers are experimenting with measles, mumps, polio, viruses that cause diarrhea and respiratory problems, viruses that afflict cattle and birds. A handful of researchers are working with bacteria, such as listeria and salmonella.
In all, more than 60 clinical oncolytic virotherapy trials are ongoing in the U.S., according to the Cancer Research Institute, a 62-year-old immunotherapy advocacy group. The trials involve cancers from breast and ovarian to prostate and pancreatic.
"It's impossible to know what's the best agent at this point, but I think the best perspective is the more options we have, the better," said M.D. Anderson's Lang. "Different tumors might respond best to different viral immunotherapies."
Experts caution that the research is effective in at best a fraction of patients and much in need of randomized trials to provide hard evidence of real benefits. Russell estimated the field is at the equivalent of mile 5 in a marathon.
Big questions remain. Do the injections work better if given before surgery so there's ample tumor tissue for the virus to grow in? Can the immune system be controlled so it doesn't kill the virus before it can proliferate through cancer cells and have its desired effect?
One big hope involves combining viral efforts with checkpoint blockade therapy, an approach pioneered by Houston scientist Jim Allison.
Allison identified a natural brake that reins in the body's defense, then developed a drug that removes the brake and unleashes the immune system to attack cancer. A network of such brakes was subsequently discovered, and scientists around the world are now investigating the best ones to target different cancers, often in combination with other therapies.
Researchers at Advantagene Inc., AdV-Tk's manufacturer, have combined the two therapies in mice and found they worked better than the viral biologic alone. Merck recently announced plans to launch an intermediate-stage trial pairing a checkpoint blockade drug with M.D. Anderson's oncolytic virotherapy.
The furthest along of the viral immunotherapies may belong to Baskin, who expects Advantagene to launch a late-stage, randomized trial of AdV-Tk in early 2016. At a major cancer conference in June, Baskin reported that 32 percent of patients who got AdV-Tk plus standard treatment in the trial that enrolled Futer survived at least three years after diagnosis, compared to 6 percent of patients who concurrently got identical treatment minus the AdV-Tk. Three of the trial's 48 patients are still alive, all more than five years out.
From the beginning, Futer had an agreement with Baskin: that he always be honest with him. If his chances of living more than a year were just 20 percent, Baskin shouldn't shade the truth. Baskin hadn't - that was the prognosis he originally gave Futer.
Studying Futer's scans before his three- and six-month follow-ups, Baskin fretted. Futer's tumor appeared bigger than it had been before surgery.
"I don't know about this," Baskin told Futer at the second appointment. "This looks bad."
Still, Baskin figured any patient with a tumor that big would be horribly impaired. Futer was doing fine - so fine he was able that summer to persuade Baskin to let him fly to England, where he was born and lived for eight years, so he could assist an old friend participating in a sheepdog trial. Baskin thought Futer's lack of symptoms suggested things might not be as they seemed.
They weren't. At one year, scans showed Futer's tumor had shrunk by a third. At two years, it was down to half its original size, and at three, just 25 percent remained. In ensuing years, the tumor melted away, culminating last month, at Futer's first appointment with Baskin in a year, when a last sliver seen on the 2014 scan was gone. Baskin had never before had a glioblastoma patient still alive nearly nine years after diagnosis.
What initially appeared to be tumor growth was actually inflammation caused by the immune system's attack on Futer's cancer, now a known hallmark of immunotherapy. The medical term is "pseudo-progression," which often precedes a positive, prolonged response to therapy.
The cancer left Futer with short-term memory issues, and he is on disability. Since his initial diagnosis, he's become extroverted and temperamental. Where he formerly had the disposition of a St. Bernard, according to his dad, he now occasionally brings to mind a German shepherd.
Futer's recovery has been an "emotional boost for everyone," Baskin said. "If I wasn't a scientist," he said, "I'd call this a miracle - and maybe it is."
At last month's appointment, Baskin and Futer looked at scans, from pre-surgery to now. Baskin floated the idea of having an immunologist analyze Futer's blood in hopes of finding clues that might suggest why he responded so well. He told of tweets doctors sent after a lecture that highlighted Futer's case.
"You're helping more people than you know," Baskin said.
"I'm having a hard time not crying," said Futer, head lowered, voice breaking.
The battle is likely not over. This spring, Futer was diagnosed with kidney cancer, unrelated to his brain tumor. A surgical team removed the mass, and for now, he is cancer-free.
In today’s session ZIOPHARM Oncology Inc. (ZIOP) registered an unusually high (1,032) contracts volume of call trades. Someone, most probably a professional was a very active buyer of the December, 2015 call, expecting serious ZIOP increase. With 1,032 contracts traded and 1073 open interest for the Dec, 15 contract, it seems this is a quite bullish bet. The option with symbol: ZIOP151218C00017000 closed last at: $0.5 or 28.6% down. The stock decreased 1.30% or $0.17 on November 13, hitting $12.94. About 2.55M shares traded hands. ZIOPHARM Oncology Inc. (NASDAQ:ZIOP) has risen 11.17% since April 14, 2015 and is uptrending. It has outperformed by 14.64% the S&P500.
Translational Scientists Issue an Immunological Call to Arms, Prepare to Overcome Cancer’s Defenses
Click Image To Enlarge +
This image depicts a group of killer T cells surrounding a cancer cell. [Alex Ritter, Jennifer Lippincott Schwartz, and Gillian Griffiths, National Institutes of Health]
In anticancer campaigns, the immune system has often shown too little fighting spirit. It can be too civilized, too restrained—unless it is specially outfitted and guided. Measures that can drive the immune system to exert itself more strenuously, more aggressively, include monoclonal antibodies, cancer vaccines, checkpoint inhibitors, and adaptive cell therapy—all the tools and techniques of immuno-oncology.
The proliferation of immuno-oncology tools and techniques was evident at the recent Translating Science into Survival conference. This event, which was held in New York City was organized by the Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research. The organizers evidently anticipated that this event, like previous immunotherapy events, would be fairly intimate. Yet it sold out quickly and ultimately strained to accommodate 1,400 attendees.
The event’s popularity was probably at least in partly due to recent immunotherapy successes against blood cancers. For example, adaptive cell therapy approaches have shown promise in small trials, and work along these lines continues apace, as several presentations demonstrated. Moreover, lessons derived from this work may be applied more broadly, even to the treatment of solid tumors.
For example, in a presentation entitled “Engineered T cells for cancer therapy,” the University of Pennsylvania’s Carl June described his team’s progress in using chimeric antigen receptor (CAR)-modified T cells to treat patients with chronic lymphocytic leukemia (CLL). “We previously reported preliminary results on three patients with refractory CLL,” Dr. June noted. “Here we report the mature results for our initial trial using CAR-modified T cells to treat 14 patients with relapsed and refractory CLL.”
The overall response rate in CLL patients was 8/14 (57%), with four complete remissions and four partial remissions. All responding patients developed B cell aplasia and experienced cytokine release syndrome, coincident with T cell proliferation. Minimal residual disease was not detectable in patients who achieved complete remission, which, Dr. June suggested, indicated that “disease eradication may be possible in some patients with advanced CLL.”
Dr. June also summarized a separate investigation that asked whether the CAR cells used against CLL would also be effective against multiple myeloma. At first glance, this may seem odd, since the CAR cells that were effective against CLL target CD19, and CD19 expression is all but absent from myeloma cells. That is, myeloma cells don’t traditionally express CD19 on their surface because they arise from the most mature type of lymphocytes—plasma cells.
Dr. June’s team, however, proceeded on the chance that they would be able to incorporate their anti-CD19 CAR T cells into a therapy that would target early precursors of myeloma cells. This therapy, which was administered to a patient with refractory multiple myeloma, involved an infusion of the patient’s own stem cells along with lymphodepleting chemotherapy (melphalan) as well as an infusion (two weeks later) of anti-CD19 CAR T cells.
The patient experienced transplantation-related side effects during the time prior to receiving CTL019. After receiving the engineered cells, she experienced no fevers or other signs of cytokine release syndrome, a condition that has been observed in other patients undergoing CTL019. At last evaluation, 12 months after treatment, the patient exhibited a complete response with no evidence of progression. According to Dr. June, “This response was achieved despite absence of CD19 expression in 99.95% of this patient’s neoplastic plasma cells.”
While the results presented by Dr. June pertain most directly to blood cancers, they may also apply more broadly. For example, they demonstrate that a “living drug” may exert its effects indirectly. Also, they emphasize the importance of managing toxicity and ensuring the expansion of modified cells. They also raise the issue of introducing cells that may demonstrate longevity.
More generally, uncertainties surrounding the differential expansion and persistence of distinct cell populations over time can complicate dosing. Similarly, with respect to toxicity, cytokine release and the generation of tumor-shredding products might be considered side effects or, really, evidence that a therapy is working.
Telling Friend from Foe
Yet engineered cells may also attack both malignant and healthy cells directly. That is, engineered cells may be sensitive to target proteins that stud both cancer cells and also, if only to a lesser degree, normal cells. In CAR T-cell therapies against leukemia and lymphoma, side effects related to direct attacks on normal cells have been manageable. Such side effects, however, may be more severe if adaptive cell therapies are directed against solid tumors.
Leading up to the Translating Science into Survival conference, Dr. June’s group published a study that described an approach for managing target-mediated toxicity. The approach, called affinity tuning, involves generating CAR T cells that are sufficiently insensitive to ignore normal cells, which are relatively target-sparse, and yet sensitive enough to latch onto cancer cells, which are relatively target-rich.
In a paper (“Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice”) that appeared September 1 in Cancer Research, the case was made that “affinity-tuned cells” could exhibit robust antitumor efficacy similar to high-affinity cells, but spare normal cells expressing physiologic target levels: “The use of affinity-tuned scFvs offers a strategy to empower wider use of CAR T cells against validated targets widely overexpressed on solid tumors, including those considered undruggable by this approach.”
Storming the Microenvironment
At the Translating Science into Survival event, the presentations concerning solid tumors emphasized that adoptive cell therapy could become more effective if obstacles in the tumor microenvironment could be overcome. For example, the University of Pennsylvania’s Ellen Puré, in a presentation entitled, “Tumor stroma: Immunomodulatory functions and a target of immunotherapy,” explained that stroma can be a barrier to T cells, including CAR T cells.
Stromal components such as fibroblasts and the extracellular matrix can play myriad functions in cancer. For example, Puré noted, reactive stroma enriched in growth and angiogenic factors presents chemoattractants that promote the recruitment of bone marrow-derived cells and can modulate inflammatory and immune cell function, all of which can contribute to its tumor-permissive nature relative to normal stroma.
“A significant portion of cancer-associated fibroblasts in virtually all human carcinomas express the cell surface protease fibroblast activation protein (FAP),” Puré continued. “Our studies indicate that FAP+ cells are required for the generation and maintenance of desmoplastic stroma and that depletion of FAP+ cells can inhibit tumor growth through both immune-dependent and immune-independent mechanisms.”
Another take on the tumor microenvironment was presented by Wolf H. Fridman, Cordeliers Research Centre, Paris. In a talk entitled, “Cancer subtypes and their immune microenvironments,” Dr. Fridman described how his group was elaborating on the Immunoscore concept, which goes back at least as far as 2006. Basically, Immunoscore builds on the insight that in many patients, the density of T cells near tumor cells could be a better predictor of survival than traditional staging based on a cancer’s size and spread.
In general, for a patient’s prognosis to be favorable, immune cells need to infiltrate a solid tumor. But recent work also suggests that more immune cells may not always be better. Apparently some immune cells are less helpful than others. Some may even be deleterious, depending on the interactions that occur between a tumor’s microenvironment and the immune system.
“Our team studied the immune infiltrates of pulmonary metastases from colorectal cancer (CRC) and renal cell carcinoma (RCC),” reported Dr. Fridman. “As in primary tumors, a high density of CD8+ T cells correlated with good prognosis for CRC metastases, while it correlated with a bad prognosis for RCC metastases.”
“In addition, in both cancer types, we identified subgroups of poor-prognosis patients with high tumoral lymphocyte infiltration, in the context of high expression of genes related to inflammation, immunosuppression, and angiogenesis,” he continued. “These results suggested that the identity of the tumor cells, rather than the organ where they grow, is critical for shaping the immune contexture of a given tumor.”
A particular cancer, then, may have an ecology of its own, one in which the overall disposition of elements—tumor cells, immune cells, extracellular matrix elements, and so on—matters, much as the overall disposition of chess pieces matters in a game of chess. Even though it might be advantageous to occupy a particular space on the board, apparently not any chess piece will do. Frustratingly, one’s own pieces may be poorly positioned, so as to get in each other’s way.
Nonetheless, as Dr. Fridman concluded, the integration of molecular and immune tumor phenotypes could guide the selection of immunotherapies “appropriate to specific, potentially responding groups of patients.”
November 13, 2015 | 2:40 pm
The Brazilian ministry of health has declared a nationwide public health emergency while doctors investigate whether a mosquito-borne disease that is new to the country is behind a sudden spike in the number of babies born with abnormally small heads.
The Zika virus is one of several possible causes being considered after one region saw a 15-fold increase in cases of microcephaly, a congenital abnormality that causes an infant's head to measure less than 33cm. Normally, the head circumference of a newborn is between 33cm and 38cm.
Depending on the severity of the condition, babies born with microcephaly often develop with cognitive problems or other developmental issues including impaired motor functions, coordination, and speech. The prognosis varies, but life expectancy is typically lower than average.
In the northeastern state of Pernambuco there have been 141 babies born with the condition so far this year, compared with a normal average of nine per year. A hospital in Recife, the state's capital, attended six of the babies on Thursday morning alone.
A health ministry spokeswoman told VICE News that the emergency alert, issued on Wednesday, was intended to channel resources for investigating the situation as a matter of urgency. She said a rapid response team was deployed to Recife to carry out clinical tests last month, when the government was first notified of the increase.
Guidelines issued by the ministry on Friday recommended that pregnant women in the northeast of Brazil attend all relevant prenatal tests and examinations, avoid alcohol and drugs, and take measures to reduce the risk of mosquito bites.
"Until the causes behind the increase in cases of microcephaly in the northeast are clarified, women who plan to become pregnant should talk confidentially to a health team. In this consultation, information and risks to the pregnancy will be evaluated to help you take your decision."
The ministry said it would be releasing an update on the situation next Tuesday.
Two other northeastern states neighbouring Pernambuco have also reported higher than usual rates of the condition that is caused by impaired brain development.
Dr Kleber Luz, an infectologist at the Federal University of Rio Grande do Norte, said there have been 22 cases of microcephaly in the state capital Natal this year compared to an average of four. He said 80% of the mothers reported symptoms suggesting they had contracted the Zika virus during the first trimester of their pregnancy.
"When the virus arrived in Natal, it surprised everyone and a lot of people got sick," he told VICE News. "It's very serious. It's something new for the scientific community and we are having meetings to investigate."
He stressed, however, that there is still no clear clinical evidence linking the condition to the virus. According to the health ministry the virus originated in Uganda and arrived in Brazil last May.
The infection is similar to dengue fever though the symptoms are less serious. They typically include high fever, a rash, and inflammation of the eyes. Patients usually recover within a week with treatment limited to painkillers and drugs to reduce the fever.
Other possible causes of the rising number of cases of microcephaly suggested so far include dengue, genetic factors, or substance abuse by the mothers.
While the phenomenon currently appears to be concentrated in the northeast, local health ministries elsewhere in the country have also announced they are on alert.
The Rio de Janeiro health authorities said they would be retrospectively investigating cases of microcephaly and reviewing reporting procedures for the future.
"We start these new protocols next week," said Rio's undersecretary of public health, Alexandre Chieppe. "We are anticipating this situation in Rio."
Meanwhile, the state government in Pernambuco said it was organising support groups for pregnant mothers who already know their babies have microcephaly and mothers of newborns with the condition.
"For us, it's very new. This has never happened before. It's a war operation," said Luciana Albuquerque, executive secretary for health surveillance in Pernambuco. "It's as much about receiving and supporting as knowing the cause."
One mother whose daughter was born with microcephaly a month ago told the news website G1 that she had a suspected case of dengue while she was pregnant.
"There were many doubts and we didn't know what caused it. It would scare anyone," she said, her identity withheld. "Now we are seeking out information and understanding what microcephaly is."
CNN)—More than eight million tourists flock to the Hawaiian islands every year. Those packing their bags need to be sure to pack mosquito repellant.
That's because state health officials are investigating a cluster of dengue fever. Thirty-three people on Hawaii's Big Island have become sick with the mosquito-borne disease since September, according to Hawaii state health officials. This is the first locally transmitted outbreak of the viral illness on the Big Island and the first outbreak in the state since five people were infected on the island of Oahu in 2011.
Twenty-five of those infected in this current outbreak are residents of the Big Island, while eight are visitors. Four children are among those who have become ill. All patients have recovered or are recovering.
The most recent case was identified on November 2. The first patient began exhibiting symptoms on September 11.
Dengue is transmitted to humans when they are bit by infected mosquitoes.
Dengue usually occurs in tropical Asia, Africa, the Caribbean and the South Pacific. The virus is not endemic in Hawaii but is sometimes brought in by infected travelers.
"It's likely an infected traveler infected the local mosquito population, which led to this cluster," state epidemiologist Dr. Sarah Park said last month.
Combatting Dengue Fever in Latin America
By Robert Crosson November 12, 2015Global Health
SEATTLE— The Aedes aegypti mosquito is a vector for several tropical diseases, most notably Dengue Fever.
Dengue fever is a tropical disease that is common in parts of Africa and Latin America. A patient displays flu-like symptoms, including head and muscle aches, vomiting, rash, nausea, a 104 degrees Fahrenheit fever and swollen glands. In the early stages, it is nearly indistinguishable from the flu.
What sets Dengue Fever apart from other illnesses is the high fever, which increases over a seven day period. The disease is most commonly found in young children and infants. For severe cases of Dengue Fever, hospitalization is the only effective treatment.
The CDC reports that Dengue Fever infects 400 million new people annually. The Pan American Health Organization reports a drastic increase in the number of cases in Latin America over the last four years.
The Pan American Organization reports that 500 million people are at risk of contracting Dengue Fever in the Americas alone.
Over 60% of the people infected with Dengue Fever are from Brazil. Brazil has registered over 700,000 cases of Dengue Fever this year. Since the epidemic started in 2009, Brazil has reported 1.3 million cases of Dengue Fever and 800 deaths.
The government of Brazil is now dealing with the source of the infection. Aedes aegypti males have been genetically modified with a gene that will render the larva dead before reaching maturity.
These genetically modified Aedes aegypti were altered by Oxitec for the Brazilian government. These Aedes aegypti are going to be released to breed with the native Aedes aegypti females in order to decrease the Aedes aegypti population.
In addition to Brazil, Mexico and the Caribbean have shown drastic increases in the number of Dengue Fever cases over the last three months.
In Bolivia, the total number of cases of Dengue Fever rose to over 6,000 this year. In response to the rising number of Dengue Fever cases, the Bolivian government has mobilized its military to clean up Santa Cruz.
Dengue Fever has begun to spread. It is not only affecting Latin America but is reaching the United States as well. The government of California reports 126 Dengue Fever cases. All of the cases have been from people who have recently traveled to Latin America.
There is currently no vaccine for Dengue Fever, but the World Health Organization is in the process of developing one. However, it is still in the testing phase and therefore not ready for public consumption.