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Precision Medicine, “My Hope for the Future”

Emily Kramer-Golinkoff

Emily Kramer-Golinkoff (A. Kotok)

7 March 2017. A meeting on Capitol Hill in Washington, D.C. today heard about one person’s struggle with cystic fibrosis and her hope for precision medicine to provide a cure. Emily Kramer-Golinkoff, co-founder of the patient advocacy group Emily’s Entourage, described her experience with cystic fibrosis and the work of her organization at a briefing on a new report on precision medicine released today by the Personalized Medicine Coalition.

Kramer-Golinkoff’s story was meant to highlight the need for precision medicine to tackle inherited diseases like cystic fibrosis featured in the report. Precision medicine takes advantage of recent advances in technology making it faster and less expensive to genetically analyze and reveal particular biomarkers or molecular indicators responsible for disease, then finding treatments addressing those indicators. In cancer, for example,  genetic analysis of tumors can reveal mutations underlying the tumor that can be addressed with drugs sometimes used to treat cancer found in other parts of the body.

For Kramer-Golinkoff, however, precision medicine has yet to find a cure for her cystic fibrosis, a genetic disease of the glands that make mucus, a substance keeping the lungs and airways moist, as well as helping prevent infection. The disease results from mutated genes passed from each parent to their children. With cystic fibrosis, the mucus becomes thick and sticky, and builds up in the lungs and airways, where the accumulation of mucus makes it easier for bacteria to grow, leading to repeated lung infections. The build-up of mucus in the other organs like the pancreas can likewise block ducts interrupting the flow of enzymes for digestion.

Emily’s Entourage, the organization in Philadelphia started by Kramer-Golinkoff offers a patient registry and raises money for research in cystic fibrosis. The group awards grants for high-impact breakthroughs designed to accelerate progress in nonsense mutations, where a mutated sequence results in an incomplete and shorter than usual protein. The group also provided seed funding for Talee Bio, a start-up company commercializing research leading to gene therapies for cystic fibrosis.

Precision medicine contributed to development of two drugs so far to treat cystic fibrosis, Kalydeco in 2012 and Orkambi in 2015, both made by Vertex that address specific mutations in the cystic fibrosis gene. Unfortunately Kramer-Golinkoff has none of the mutations addressed by the drugs. Nonetheless, she told the meeting, “Personalized medicine is my hope for the future.”

The document, “Personalized Medicine Report: Opportunity, Challenges, and the Future,” released by Personalized Medicine Coalition at the meeting and provided to Science & Enterprise tells of a 62 percent increase since 2012 in the number of precision medicines on the market. The report lists 132 drugs and their corresponding biomarkers approved as of September 2016. Most of the drugs in the inventory are for cancer, cardiac conditions, psychiatric disorders, and infectious diseases. The report also indicates that a recent review finds some 65,000 different genetic tests are also on the market, making genetic data much more widely available than before.

In addition, the report highlights changes in regulations and reimbursement practices that could clear away obstacles to adoption of precision medicine. In the discussion of the report, Michael Sherman, chief medical officer of Harvard Pilgrim Health Care, a not-for-profit health plan serving New England, noted regulations should provide incentives for rewarding value, which would support more use of diagnostics combined with treatments that make up precision medicine.

Instead, says Sherman, you often find unintended consequences of regulations like Medicaid’s “best price” rules that require Medicaid to pay the lowest price charged for comparable goods or services. When companion diagnostics are included in the price of a drug, the cost of those tests to Medicaid is $0.00, providing no incentive for increased diagnostics required in precision medicine. Jay Wohlgemuth, chief medical officer of Quest Diagnostics and another panel member, confirmed that reimbursement practices focusing on individual services particularly discourage diagnostics, and he urged more reimbursement practices for overall treatment strategies.

Sen. Edward Markey

Sen. Edward Markey (A. Kotok)

Keynote speaker, Senator Edward Markey, Democrat from Massachusetts, pointed out more serious headwinds threatening precision medicine and U.S. health care in general. Markey said the Trump Administration’s proposed $54 billion increase in defense spending, coupled with $20 billion for a border wall with Mexico, will require compensating cuts in non-defense discretionary programs, such as medical research.

In addition, the threatened repeal of the Affordable Care Act, often called ObamaCare, will degrade the quality of U.S. health care. Markey noted the experience of Massachusetts that began a similar statewide program before passage of the Affordable Care Act, which now gives the state the highest rate of insurance coverage and most favorable health outcomes in the country, while still enjoying only a 3 percent unemployment rate.

He also underscored that Massachusetts may be known as the Bay State, but it is also the “brain state” which benefits from health research spending. Massachusetts, said Markey, has 2 percent of the U.S. population, but manages to attract 11 percent of NIH’s research grants.

Update, 7 March 2017: The report is now online.

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Process Converts Food Waste to Auto Tire Materials

Katrina Crnish and Cindy Barrea

Katrina Cornish, left, and Cindy Barrera examine ground tomato skins and egg shells. (Kenneth Chamberlain, Ohio State University)

7 March 2017. Agricultural scientists in Ohio are developing a process for converting common food waste into materials used in car tires, and filed a patent for these techniques. The lab of biomaterials professor Katrina Cornish at Ohio State University also started a spin-off enterprise to commercialize their discoveries for producing rubber products from alternative sources.

Cornish and colleagues study the production of bio-based materials that can substitute for imported rubber, a vital material for a wide range of consumer and industrial goods. Natural rubber, however, is derived largely from one plant species, Hevea brasiliensis, native to South America and grown commercially as well in southeast Asia and west Africa. Cornish’s lab cites data showing that the U.S. could face a shortfall of 1.5 metric tons of imported rubber by 2020, due largely from increasing global demand, creating a need for domestic raw material sources.

Researchers in the lab are already investigating methods for converting common plants and even those considered weeds growing in North America into raw materials for rubber. Among those materials are guayule, a flowering plant in the southwestern U.S. and Mexico,. Cornish and colleagues are developing guayule into an alternative for latex rubber used in stretchable products like gloves and condoms. In addition, attempts to make rubber from dandelions go back as far as the early 20th century, but Cornish’s lab is studying a variation of a dandelion native to Kazakhstan in central Asia that they call Buckeye Gold, which has roots that can produce rubber nearly identical to Hevea plants.

As part of these studies, the researchers are also looking into replacements for additives used in making rubber products, such as car tires. About 30 percent of the content of car tires is carbon black, a derivative of carbon made from heavy oil or natural gas into particles that mix with rubber to improve its durability and give tires their black color.  And just as the need for natural rubber is growing with the expanding world economy, the need for carbon black is growing as well, thus the need for domestic alternatives.

Cornish’s lab discovered alternatives to carbon black that provide durability for tires in common waste items from food, such as egg shells and tomato skins. Research by Cindy Barrera, a postdoctoral fellow in the lab, shows egg shells have a porous microstructure that offer a larger surface area to bind with rubber molecules, while tomato skins are stable at high temperatures, a key property for tires. Both egg shells and tomato skins are available in large quantities as waste items from food products manufacturers.

“Fillers generally make rubber stronger, but they also make it less flexible,” says Barrea in a university statement. “We found that replacing different portions of carbon black with ground egg shells and tomato peels caused synergistic effects — for instance, enabling strong rubber to retain flexibility.” Colleagues in the lab are studying other additives to keep tires black in color, rather than the reddish-brown hue from egg shells and tomato skins.

Ohio States technology transfer office filed for a patent on processes to replace carbon black and other additives with natural products, such as food wastes. Cornish and Barrea are among the inventors listed on the document. Cornish is also the founder of the company EnergyEne in Wooster, Ohio licensing the rights to this patent from Ohio State for commercial development. EnergyEne is already developing commercial techniques for deriving latex rubber from guayule plants, and received a small business technology transfer grant from National Science Foundation to support its work.

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Air Sampling Device Finds Unreported Allergens


Pollen (Wikimedia Commons)

6 March 2017. A system designed to sample the air in homes of people with allergies found a number of airborne allergens in residences that previously went undetected by other devices. The founders of Inspirotec LLC, based in Chicago, reported on test results of the company’s exhale system in a session on Sunday, 5 March at the annual meeting in Atlanta of the American Academy of Allergy, Asthma, & Immunology.

The presentation, by Inspirotec founders Prasanthi Ghandi and Julian Gordon, and Paul Detjen, a Chicago allergist, describes a test of the company’s system with individuals having asthma and hay fever. Asthma is a chronic condition where the airways become inflamed and narrow, causing people to experience wheezing, shortness of breath, tightness in the chest, and coughing for periods of time. Centers for Disease Control and Prevention estimates that in 2010 some 18.7 million adults had asthma, along with 7 million children.

Hay fever, also called seasonal allergic rhinitis, causes symptoms similar to the common cold:  runny nose, itchy eyes, congestion, sneezing and sinus pressure. While the common cold is usually caused by a virus, hay fever is an allergic reaction to pollen, dust mites, pet dander, and other allergens found indoors and outdoors.

Inspirotec’s exhale system samples air in homes for allergens that the company says is superior to current methods that analyze dust from the environment as a surrogate for the air actually breathed by people with allergies. The device plugs into a standard wall outlet and runs for 5 days. It uses electrostatic particle technology to sample the air at a rate the company says is 8 times faster than normal breathing. Electric currents capture biological matter, including mites, hair, pollen, fungi, bacteria, and viruses.

Users of the system then send the device back to Inspirotec, and answer a questionnaire about personal health and their environment. Inspirotec uses laser-based analytical techniques to quantify allergens in homes where the device was run, which the company reports to the user in a personal profile, as well as compared to similar individuals with allergies or to previous samples.

At the Atlanta meeting, the Inspirotec team reported on results from 92 individuals served by 5 allergists in or near Chicago. The 92 participants ran the exhale devices in their bedrooms for 5 days, which provided samples that the company analyzed for 12 common household allergens such as from dust mites, dogs, cats, mice, mold, cockroaches, and pollen. Participants also completed health and environment surveys.

The results show expected correlations between Inspirotec device readings and number of pets, as well as humidity and presence of dust mites, and use of high-efficiency particulate air or HEPA filters to clean the air with fewer allergens. But the results also show in some cases the presence of cat or dog allergens in homes without those pets, as well as dust mite and cockroach allergens that were not previously found in those homes. The company says the results will be used to provide baseline measures to use in future data gathering, and to compare with other regions.

As reported by Science & Enterprise, Inspirotec was among the first group of companies in 2012 supported by Breakout Labs, a revolving investment fund in San Francisco that aims to support early-stage enterprises developing new technologies. Breakout Labs is backed by the Thiel Foundation, established by entrepreneur Peter Thiel, a founder of online payments service PayPal and an early investor in Facebook.

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Trial Underway to Test Cancer Immunotherapy Aid

Cancer in headline


6 March 2017. A clinical trial began recruiting participants with advanced tumors to test a compound that helps treatments for cancer harnessing the immune system. The study, conducted by biotechnology company Deciphera Pharmaceuticals LLC in Waltham, Massachusetts, is testing its experimental drug code-named DCC-3014.

Deciphera Pharmaceuticals develops small molecule, or low molecular weight, drugs that act against enzymes encouraging the growth and spread of cancers. The company maintains a library of compounds designed to deactivate these enzymes and keep them switched off, and develops drugs from those compounds to address resistance to cancer therapies or inhibitors preventing the immune system from acting against cancer.

DCC-3014 is in the latter category, designed to target macrophages, white blood cells in the immune system that normally attack and absorb invading pathogens. In this case, cancer hijacks macrophages and uses them to keep the immune system from attacking the cancer. DCC-3014 acts against these hijacked macrophages by blocking a key protein known as colony stimulating factor 1, or CSF-1, receptor. These CSF-1 receptor proteins are found on the surface of many cell types, but with cancer the proteins cause macrophages to prevent rather than activate the immune system from fighting the cancer.

Deciphera designed DCC-3014 to stop macrophages acting as checkpoints that prevent the immune system from fighting tumors. The company says preclinical studies show DCC-3014 stops solid tumor growth working on its own or added to other checkpoint inhibitors in mice induced with colorectal or prostate cancer. The findings also show DCC-3014 works only on CSF-1 receptor proteins, and spares other related enzymes.

“Preclinical data from a number of cancer models have demonstrated that DCC-3014 has potent macrophage checkpoint inhibitory activity,” says Michael Taylor, Deciphera’s president in a company statement. “We believe DCC-3014 has great potential as a novel immunomodulatory agent and an important new therapy for cancer patients.”

The early-stage clinical trial is recruiting 55 individuals, age 16 and over, with advanced solid tumor cancers,  at Sarah Cannon Research Institute in Nashville. The trial may also enroll some patients with blood-related cancers, such as leukemia. The study will evaluate DCC-3014’s safety at various dosage levels, looking for signs of adverse effects and seeking out the maximum tolerated dose. The trial is also tracking chemical activity of DCC-3014 in the body, as well as levels of white blood cells like macrophages dependent on CSF-1 receptor proteins.

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Messenger RNA Engineered to Produce Antibodies

RNA molecule illustration

RNA molecule illustration (Nicolle Rager Fuller, National Science Foundation)

3 March 2017. Academic and industry researchers demonstrated production of therapeutic antibodies inside cells of lab mice, offering a simpler and lower-cost alternative to monoclonal antibodies. The team led by University of Pennsylvania immunologist Drew Weissman describes its technology in the 2 March issue of the journal Nature Communications.

Monoclonal antibodies, synthetic proteins designed to treat disease by neutralizing proteins responsible for the condition, are a fast-growing segment of the pharmaceutical industry for treating diseases including cancer and autoimmune disorders. These synthetic antibodies, however, are costly to develop and often expensive for patients. An emerging option to synthetic antibodies is gene therapy that uses adeno-associated viruses to deliver antibody-producing genes to counter disease-causing proteins. While adeno-associated viruses are considered benign, they still present safety risks for some patients, including unwanted immune responses.

In their paper, Weissman and colleagues demonstrated another alternative, engineered messenger ribonucleic acid or mRNA, a nucleic acid related to DNA with the instructions used by cells to produce the amino acids in proteins for carrying out functions in the body. The researchers — with team members from UPenn’s medical school and biotechnology companies BioNTech AG in Mainz, Gemany and Acuitas Therapeutics in Vancouver, British Columbia — evaluated harnessing mRNA to deliver the instructions for producing therapeutic antibodies inside cells, rather than delivering antibodies created outside the body.

In its natural state, however, mRNA would present the same problems some patients encounter with adeno-associated viruses, namely immune reactions such as inflammation. To overcome this obstacle, the researchers encased mRNA in nanoscale lipid capsules, a technique devised by post-doctoral researcher Norbert Pardi and doctoral candidate Michael Hogan, co-authors of this paper and tested earlier with an mRNA vaccine candidate for the Zika virus. Acuitas Therapeutics is commercializing this technology and prepared the lipid nanoparticles for this project.

In the study, the team demonstrated delivery of mRNA to produce an antibody protecting against the HIV virus that causes AIDS. The antibody, known as VRC01, addresses a common target found across multiple strains of HIV, and is being tested both as a treatment and protective vaccine for HIV. Cost to patients is a key issue with HIV medications, and a synthetic VRC01 antibody would likely be too expensive for many patients and public health agencies.

The researchers tested mRNA encoding VRC01 antibodies in lab mice induced with compromised immune systems and thus highly susceptible to HIV infections. Within 24 hours following a single injection of the lipid nanoparticles with mRNA, the mice showed higher concentrations VRC01 antibodies in their blood. And with weekly injections, the mice could maintain a basic threshold level of VRC01.

The team also tested the ability of the mRNA in lipid nanoparticles encoding VRC01 to protect against HIV viruses. The researchers found small vaccine-style quantities of these nanoparticles could protect against two different HIV strains. For comparison, doses 40 times larger were needed to provide the same protection against HIV infections, when directly injecting VRC01 antibodies.

Weissman believes encoding mRNA to produce antibodies in cells may be safer for patients than some biotechnology manufacturing practices. “Biotech manufacturing,” says Weissman in a university statement, “requires a cell line and extensive purification that can aggregate or misfold the protein, resulting in an unwanted immune response against the protein or other adverse events.”

Nonetheless, biotech companies are exploring this technology. Katalin Kariko, an adjunct professor at UPenn and  co-author of the paper, is vice-president of BioNTech, a company developing therapies from synthetic forms of mRNA. As reported in Science & Enterprise, the Genentech division of the Roche Group, is licensing BioNTech’s mRNA technology for cancer treatments.

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Biotech Companies to Discover Ebola, Zika Vaccines

Ebola clinic

Woman being evaluated at an Ebola clinic in Sierra Leone (Rebecca Rollins, Partners In Health)

2 March 2017. Two biotechnology companies are collaborating to discover new vaccines protecting against Ebola and Zika viruses that present global threats to public health. This project is the second partnership between Integral Molecular in Philadelphia and Integrated BioTherapeutics in Rockville, Maryland dealing with urgently needed vaccines.

The Ebola outbreak in 2014-15 caused a serious public health emergency in West Africa, with nearly 29,000 cases reported in Liberia, Sierra Leone, and Guinea, leading to more than 11,000 deaths. The disease is caused by a virus spread through direct contact, often through broken skin or mucous membranes, with a sick person’s blood or bodily fluids, contaminated objects such as needles, and infected animals. No treatments or vaccines for Ebola are yet approved, although World Health Organization says 2 vaccine candidates are being evaluated.

The Zika outbreak is a current public health challenge, with an outbreak in Brazil spreading to the Caribbean and the Americas, including the U.S. mainland. The Zika virus is transmitted primarily by aedes aegypti mosquitoes, the same species carrying chikungunya, dengue, and yellow fever pathogens. The virus may also be spread through sexual contacts. Most people contracting the Zika virus report symptoms such as mild fever, conjunctivitis or pink eye, and muscle and joint pain.

The current Zika outbreak, however, is resulting in increasing numbers of cases of birth defects, notably microcephaly and Guillain-Barré syndrome. Centers for Disease Control and Prevention counts more than 5,000 Zika cases in the 50 U.S. states and District of Columbia, and almost 37,500 cases in U.S. territories. As with Ebola, no treatments or vaccines are yet available.

Both Integral Molecular and Integrated BioTherapeutics develop vaccines for infectious diseases. Integral Molecular’s technology addresses proteins generated by viruses with outer lipid membranes or envelopes that attach and transmit viral proteins to the host cells. In this project, Integral Molecular plans to screen its panel of viral envelope protein variants to find optimal targets for Ebola and Zika vaccines.

Integrated BioTherapeutics discovers and develops vaccines for infectious diseases, with a technology focusing on carbohydrate-based proteins and virus-like particles. The company has a separate infectious disease testing service with established models for Zika and other pathogens. In this collaboration, Integrated BioTherapeutics will conduct preclinical tests of vaccine candidates.

The two companies previously worked together with Mapp Biopharmaceutical in San Diego and researchers from several universities and research institutes to create a synthetic antibody to protect against the two main strains of the Ebola virus. That antibody, code-named FVM04, extends the ZMapp antibodies to address the Sudan Ebola variation, while still covering ZMapp’s original Zaire strain.

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Mobile App-Controlled Patch Reduces Migraine Pain

Nerve cells illustration


2 March 2017. A patch worn on the arm providing stimulation to nerve cells was shown in a clinical trial to reduce the amount of pain experienced by people with migraines. Results of the trial appear in the 1 March issue of the journal Neurology (paid subscription required), published by American Academy of Neurology.

The trial tested a system made by Theranica Bio-Electronics, a company in Netanya, Israel developing devices to control pain, beginning with migraine, using neuromodulation, or electronic stimulation of circuits in the nervous system. Migraine is a neurological syndrome causing severe headaches along with nausea, vomiting, and extreme sensitivity to light and sound. In some cases, migraines are preceded by warning episodes called aura including flashes of light, blind spots, or tingling in arms and legs. The web site estimates 37 million people in the U.S. suffer from migraines, and cites World Health Organization data indicating migraines affect 18 percent of American women and 7 percent of men.

Theranica’s system consists of a patch worn on the upper arm with a miniature battery, chip, and electrodes emitting painless, weak electronic impulses designed to block pain signals from reaching the brain. The device is controlled wirelessly with a smartphone app. People with the device are asked to apply the patch and start the device when they begin experiencing a migraine and wear it for 20 minutes. The company says the chip also processes feedback from motor neurons, and has safety features to detect, for example, improper placement of the patch.

The clinical trial was led by David Yarnitsky, a professor of neurology at Technion-Israel Institute of Technology in Haifa, and a medical advisor to Theranica. The study enrolled 71 individuals who experienced between 2 and 8 migraine episodes a month. Participants were asked to use the Theranica device for 20 episodes, as well as refrain from using pain medication for 2 hours after using the device.

The system used in the trial was programmed to randomly emit impulses at 3 levels of stimulation, as well as a non-stimulating sham signal for comparison. For this study, the 71 systems captured data on 299 migraine episodes, where participants rated their migraine pain levels on the smartphone app. Data from the devices were transmitted without personal identification to a remote database for analysis.

The results show nearly two-thirds (64%) of participants receiving stimulation at the 3 active levels experienced reductions in pain by 50 percent or more in the 2 hours following treatment, compared to about a quarter (26%) receiving a non-stimulating signal. More than half (58%) of individuals experiencing severe to moderate pain in their migraine episodes found their pain reduced to mild levels or no pain when receiving the highest stimulation level. Again, only about a quarter (24%) of those receiving non-stimulating signals experienced similar pain reductions.

More participants starting the stimulation within 20 minutes of an episode (47%) experienced reductions in pain, compared to those who started the device after 20 minutes (25%). However, many participants turned off the device during the non-stimulating signals, when they discovered the signals were not reducing their pain.

“People with migraine are looking for non-drug treatments,” says Yarnitsky in an American Academy of Neurology statement, “and this new device is easy to use, has no side effects, and can be conveniently used in work or social settings.”

Theranica says migraine is the first target of its non-drug pain technology. The company plans to expand its use to other types of acute and chronic pain, including muscle soreness.

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Cancer Blood Test Company Raises $65M in Early Funds

Blood sample

(Public Domain Pictures/Pixabay)

1 March 2017. Freenome, a company applying machine learning to analysis of liquid biopsies, is raising $65 million in its first round of venture financing. The funding round for the 3 year-old enterprise in South San Francisco, California, is led by technology investment company Andreessen Horowitz.

Freenome’s founders, veterans of other health care and life science companies, began the enterprise to improve the state of cancer diagnostics, making it possible to discover cancer earlier in the development of the disease, when individuals have more treatment and even prevention options. The company uses the term “freenome” as well to describe the cell-free genetic material floating in the blood stream, which makes up some of the raw material it analyzes for cancer diagnostics.

The problem faced by many current cancer screening methods, such as prostate-specific antigens or PSAs for prostate cancer and mammograms, says Freenome, is their imprecision that leads to erroneous results, such as false-positives, resulting in unnecessary procedures such as biopsies, and even treatment.  Part of the problem with current screening methods, says the company, is the application of simplified models to understand a dynamic, complex disease such as cancer. Moreover, physicians need to know more information about the particular disease than just its presence or absence in the patient.

The technology developed by Freenome combines genomics, computational biology, and artificial intelligence to analyze simple blood samples for this dynamic, complex environment. Rather than focusing on a few genetic mutations suspected of causing a person’s cancer, Freenome’s process analyzes the full gamut of molecular clues in the blood, looking for evidence of immune-system or metabolic changes, as well as DNA from cells emitted by a tumor.

Freenome’s technology is built on its adaptive genomics engine that applies deep learning, an artificial intelligence and machine learning process, to discern underlying patterns in relationships, and build those relationships into knowledge bases found today in a number of disciplines. In this case, the adaptive genomics engine seeks to identify unique molecular signatures that not only detect the presence of cancer, but also provide a detailed picture of the disorder for the cancer specialist to prescribe a precise course of treatment. By making the test simple and accurate, says the company, many cancers could be caught earlier and treated successfully.

Freenome’s co-founder Gabriel Otte believes the technology may even have enough power and precision to find indicators of potential cancer early enough in the process to take steps to prevent the disease from occurring. “One day,” says Otte in a company blog post, “not only will we be able to find diseases BEFORE they happen, but we may be able to suggest next steps that will empower patients to avoid those diseases on their own.”

Otte says Freenome is working with researchers at University of California in San Francisco and San Diego, as well as Massachusetts General Hospital to further refine the technology. “We are also working with five pharmaceutical companies,” Otte adds, “to give an accurate indication of the treatments that a patient would most likely to respond to once we’ve detected the cancer.”

Andreessen Horowitz, a seed-round investor, is leading Freenome’s venture round, joined by seed investors Data Collective and Founders Fund. Joining in the round are new investors Google Ventures, Polaris Partners, Innovation Endeavors, Asset Management Ventures, Charles River Ventures, and Spectrum 28. Freenome raised $5.6 million in its seed round in June 2016.

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Engineered T-Cells Shown Reducing Non-Hodgkin Lymphoma

Human T-cell lymphocyte

Scanning electron micrograph of a human T-cell lymphocyte (National Institute of Allergy and Infectious Diseases, NIH)

1 March 2017. A clinical trial testing synthetic immune system cells shows after 6 months the cells can generate a full or partial response in many patients with non-Hodgkin lymphoma. The trial, testing a therapy for blood-related cancers known as axicabtagene ciloleucel made by Kite Pharma, also reported a continuing problem of high adverse event rates among participants.

Kite Pharma, in Santa Monica, California, develops personalized treatments for cancer with synthetic T-cells from the patient’s own immune system. The treatments in this case address non-Hodgkin lymphoma, a cancer of lymph tissue that forms part of the body’s immune system. There are different types of non-Hodgkin lymphoma reflecting different types of white blood cells. Most adults with the disorder have either diffuse large B-cell lymphoma, which is usually aggressive, and follicular lymphoma, a slower growing cancer.

Axicabtagene ciloleucel takes T-cells from the patient, then genetically engineers the cells to produce chimeric antigen receptors on the cell surface that attract an antigen — a protein generating antibodies — fighting the cancer. The engineered T-cells are then grown in the lab in large quantities and infused back into the patient, where they attract the antigen proteins and fight the cancer. Early clinical trials of this technique, known as CAR-T says National Cancer Institute, show the technique has promise against advanced blood-related cancers, such as non-Hodgkin lymphoma.

Kite Pharma yesterday reported results from a 6-month follow-up review of participants in an early- and intermediate-stage clinical trial testing the treatment’s safety and efficacy in patients with aggressive cases of diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal large B-cell lymphoma (PMBCL), a rare form of the disease. The study tested for complete or partial response to the treatments with standard diagnostic definitions following the treatments and over one year, as well as watching for adverse reactions.

Of the 101 participants in the trial, 36 percent achieved a complete response from the treatments after 6 months, while another 5 percent showed a partial response. Those percentages are down from response rates reported immediately after the treatments, where more than half (54%) showed a complete response and 28 percent a partial response. Response rates were somewhat higher for TFL or PMBCL forms of the disease, where half of the group reported a complete response after 6 months.

Among patients with DLBCL, the most common form of the disease, 31 percent after 6 months were shown with a complete response. In addition, Kite Pharma says to date, the median overall survival time of patients in the trial, standing at 8.7 months, has not yet been reached.

As noted by Science & Enterprise in September 2016, many participants in this trial had serious adverse effects from the treatments after 3 months, and that pattern continued in the 6-month follow-up. Between 20 and 43 percent of participants reported side effects at least severe enough to require hospitalization from anemia, low white blood counts, low platelet counts, encephalopathy or altered brain functions, and lower lymphocyte counts.

Compared to the 3-month report, says Kite Pharma, rates of severe cytokine release syndrome and related neurological events decreased. Cytokine release syndrome occurs when enzymes are emitted from cells targeted by treatments, causing flu-like symptoms such as fevers, nausea, and muscle pain, but also neurological symptoms including hallucinations and delirium.

In our September story, we reported on 2 deaths among participants in the trial related to the treatments from hemophagocytic lymphohistiocytosis, a rare life-threatening disorder from overactive immune system cells, and cardiac arrest. The company says a third death occurred among participants, from a pulmonary embolism or blood clot in the lungs, which was unrelated to the treatments.

Axicabtagene ciloleucel received a breakthrough therapy designation in December 2015 from Food and Drug Administration for the three types of non-Hodgkins lymphoma in the clinical trial. FDA grants a breakthrough designation for new therapies to treat serious or life-threatening conditions that demonstrate substantial improvements over current treatments. Kite Pharma plans to provide full results from the trial in April at a meeting of the American Association for Cancer Research.

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Trial Begins Testing Enhanced Cord Blood Stem Cells


(Sasin Tipchai, Pixabay)

28 February 2017. A clinical trial testing transplant grafts derived from umbilical cord blood as an alternative to bone marrow stem cells for people with blood-related cancers is treating its first patient. The trial is conducted by Gamida Cell Ltd., a biotechnology enterprise in Jerusalem, Israel.

Gamida Cell develops therapies for cancer and inherited diseases derived from engineered cells, including stem cells, with sources such as umbilical cord blood. One of the company’s technologies enhances umbilical cord blood with nicotinamide, a natural compound related to vitamin B3 used in some cases as a sensitizing agent for chemo- or radiation therapy that expands blood flow to treat cancerous tumors.

The company applies nicotinamide to its NiCord product designed as an alternative to bone marrow transplants for people with blood-related cancers such as leukemia. A leading treatment for these cancers is a bone marrow transplant that delivers healthy stem and progenitor cells to the patient. But bone marrow transplants require a full genetic match that often makes it difficult to find a donor.

NiCord is derived from umbilical cord blood, which in its natural state has some stem and progenitor cells, but not enough for blood-related cancer treatments. Gamida Cell enhances umbilical cord blood with nicotinamide to expand the quantity of stem and progenitor cells, as well as improve their functionality and grafting ability to bone marrow, then added to cord blood mixed with bone marrow and lymphoid cells. NiCord treatments are produced on demand in Gamida’s manufacturing facilities then shipped frozen to the patient’s bedside, a process the company says takes 3 weeks.

The late-stage clinical trial is enrolling 120 individuals age 16 to 60 with various blood-related cancers at 9 sites in the U.S. and Europe. Participants will be randomly assigned to receive NiCord or regular umbilical cord blood treatments for comparison. The main outcome indicator of the study is time needed for treatments to graft to neutrophils, the most abundant type of white blood cell, up to 42 days following the transplants.

Gamida Cell conducted early and intermediate-stage trials of NiCord treatments, with outcomes the company hopes to confirm in the new trial. NiCord transplants are recognized by the Food and Drug Administration and European Medicines Agency as orphan treatments for rare diseases. FDA also designated NiCord transplants as a breakthrough therapy in October 2016, signifying a treatment for serious or life-threatening condition, where early clinical evidence indicates a substantial improvement over available therapies. A breakthrough designation gives the product more intensive attention from FDA and an accelerated review schedule.

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