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A new HER2 mutation, a clinical trial and a promising diagnostic tool for metastatic breast cancer

There is a group of metastatic breast cancers that has the HER2 gene amplified – the cells have many copies of it – which leads to enhanced activity of the product enzyme, a tyrosine kinase. HER2 has been established as a therapeutic target in breast cancer, and breast cancers in which the HER2 gene is not amplified do not, in general, respond to HER2-directed therapeutic approaches.

A few years ago, when the research teams of Dr. Matthew Ellis and others carried out a molecular characterization of breast cancer tumors, they found a new mutation in HER2 that was different from gene amplification but also resulted in tyrosine kinase being constantly activated.

“In this particular activation mechanism, the cells develop a subtle mutation within the functional part of the HER2 gene that activates the enzyme,” said Ellis, professor and director of the Lester and Sue Smith Breast Center, part of the National Cancer Institute-designated Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine. “The mutation locks the enzyme into an ‘on’ position.”

Ellis and his colleagues developed a preclinical model to study this new HER2 mutation and discovered that the enhanced enzymatic activity could trigger tumor formation. Furthermore, these tumor cells were sensitive to an experimental drug, neratinib. With this information in hand, the researchers took the next step.

“We launched a phase II clinical trial of neratinib in patients with metastatic breast cancer carrying a HER2 mutation,” Ellis said. “Finding patients that are positive for a HER2 mutation required a national collaboration because we had to screen hundreds of patients to identify the 2 to 3 percent that have a tumor driven by a HER2 mutation. The results of the clinical trial were encouraging in that about 30 percent of the 16 patients treated with neratinib had a meaningful clinical response showing significant disease stabilization or regression. Neratinib was well tolerated by most patients.”

“This is the first time we had a reasonable number of patients treated for HER2 mutations in whom we could estimate the response rate.”

The number of patients who could potentially benefit from this new treatment approach is estimated to be in the thousands. The researchers estimate that as many as 200,000 patients are likely to be living with metastatic breast cancer today in the United States. Based on the estimate that the new mutation is present in 2 to 3 percent of cases, the researchers calculated that approximately 4,000 to 6,000 patients with metastatic breast cancer carry a HER2 mutation and are therefore potential candidates for neratinib treatment.

Circulating tumor DNA analysis, a promising diagnostic tool

To identify the patients in this study who carried the new HER2 mutation, the researchers required tissue from the tumor, a biopsy, from which they could extract and sequence the genetic material to determine the presence of the HER2 mutation. This task turned out to be a major challenge because for 20 to 30 percent of the patients the researchers did not have sufficient material to make the diagnosis.

“To assist in our ability to identify patients with HER2 mutation-positive tumors, we conducted circulating tumor DNA analysis,” Ellis said. “The tumor’s DNA is released into the human bloodstream, and we were able to determine the presence of the mutation in blood samples from the patients. Importantly the circulating tumor DNA results were highly concordant with the tumor sequencing results, and they were much easier to determine. Notably, the blood test was sensitive enough that we could use it as a tool to determine eligibility for the clinical trial.”

In addition to bringing to the table a novel treatment for metastatic breast cancer carrying a HER2 mutation, the researchers have tested the value of the circulating tumor DNA as a disease-monitoring marker.

“A circulating tumor DNA-based blood test also could therefore be potentially used to monitor tumor progression and to determine whether patients are responding or not to treatment after just one month of therapy,” Ellis said.

Ellis also is a McNair Scholar at Baylor.

Read all the details of this study, the full list of contributors and their financial support in Clinical Cancer Research.

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A new HER2 mutation, a clinical trial and a promising diagnostic tool for metastatic breast cancer

There is a group of metastatic breast cancers that has the HER2 gene amplified – the cells have many copies of it – which leads to enhanced activity of the product enzyme, a tyrosine kinase. HER2 has been established as a therapeutic target in breast cancer, and breast cancers in which the HER2 gene is not amplified do not, in general, respond to HER2-directed therapeutic approaches.

A few years ago, when the research teams of Dr. Matthew Ellis and others carried out a molecular characterization of breast cancer tumors, they found a new mutation in HER2 that was different from gene amplification but also resulted in tyrosine kinase being constantly activated.

“In this particular activation mechanism, the cells develop a subtle mutation within the functional part of the HER2 gene that activates the enzyme,” said Ellis, professor and director of the Lester and Sue Smith Breast Center, part of the National Cancer Institute-designated Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine. “The mutation locks the enzyme into an ‘on’ position.”

Ellis and his colleagues developed a preclinical model to study this new HER2 mutation and discovered that the enhanced enzymatic activity could trigger tumor formation. Furthermore, these tumor cells were sensitive to an experimental drug, neratinib. With this information in hand, the researchers took the next step.

“We launched a phase II clinical trial of neratinib in patients with metastatic breast cancer carrying a HER2 mutation,” Ellis said. “Finding patients that are positive for a HER2 mutation required a national collaboration because we had to screen hundreds of patients to identify the 2 to 3 percent that have a tumor driven by a HER2 mutation. The results of the clinical trial were encouraging in that about 30 percent of the 16 patients treated with neratinib had a meaningful clinical response showing significant disease stabilization or regression. Neratinib was well tolerated by most patients.”

“This is the first time we had a reasonable number of patients treated for HER2 mutations in whom we could estimate the response rate.”

The number of patients who could potentially benefit from this new treatment approach is estimated to be in the thousands. The researchers estimate that as many as 200,000 patients are likely to be living with metastatic breast cancer today in the United States. Based on the estimate that the new mutation is present in 2 to 3 percent of cases, the researchers calculated that approximately 4,000 to 6,000 patients with metastatic breast cancer carry a HER2 mutation and are therefore potential candidates for neratinib treatment.

Circulating tumor DNA analysis, a promising diagnostic tool

To identify the patients in this study who carried the new HER2 mutation, the researchers required tissue from the tumor, a biopsy, from which they could extract and sequence the genetic material to determine the presence of the HER2 mutation. This task turned out to be a major challenge because for 20 to 30 percent of the patients the researchers did not have sufficient material to make the diagnosis.

“To assist in our ability to identify patients with HER2 mutation-positive tumors, we conducted circulating tumor DNA analysis,” Ellis said. “The tumor’s DNA is released into the human bloodstream, and we were able to determine the presence of the mutation in blood samples from the patients. Importantly the circulating tumor DNA results were highly concordant with the tumor sequencing results, and they were much easier to determine. Notably, the blood test was sensitive enough that we could use it as a tool to determine eligibility for the clinical trial.”

In addition to bringing to the table a novel treatment for metastatic breast cancer carrying a HER2 mutation, the researchers have tested the value of the circulating tumor DNA as a disease-monitoring marker.

“A circulating tumor DNA-based blood test also could therefore be potentially used to monitor tumor progression and to determine whether patients are responding or not to treatment after just one month of therapy,” Ellis said.

Ellis also is a McNair Scholar at Baylor.

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New combination of anti-obesity drugs may have beneficial effects

Research conducted in the Perelman School of Medicine at the University of Pennsylvania has revealed that a unique combination of hormone-based drugs can produce enhanced weight loss in laboratory tests with obese animals. The research is to be presented this week at the Annual Meeting of the Society for the Study of Ingestive Behavior (SSIB), the foremost society for research into all aspects of eating and drinking behavior.

“Imagine a drug regimen where an obese person would cycle between different drug therapies over the course of a month to achieve a greater degree of body weight loss compared to the effects achieved with either a single drug or the continuous combination of drugs,” said senior author Dr. Matthew Hayes. His team studied the combination of two different drug classes that target different hormones: amylin and glucagon-like peptide-1 (GLP-1). They found that combined treatments acted synergistically to suppress feeding and body weight. They also discovered that the weight loss effects of chronic amylin- and GLP-1-based combination therapies could be enhanced when obese lab animals are cycled through their drug treatments. “The idea of drug-cycling is nothing new,” says lead author Kieran Koch-Laskowski. “Millions of women on birth control pills, for example, already take daily pills that cycle between drug and placebo throughout the month,” she goes on to say.

Perhaps the most exciting finding of the current data coming out of Penn is the fact that the research finds these enhanced weight loss effects with a combination of drugs that are either already FDA approved or in clinical trials for metabolic diseases, “making the translational impact of our work extremely timely and highly clinically relevant!” says Hayes. The authors are now finalizing their research to demonstrate mechanically how these two hormonal systems interact to achieve greater weight loss in the hopes of fast-tracking their findings to new clinical treatments for obesity.

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Genetically enhanced, cord-blood derived immune cells strike B-cell cancers

Immune cells with a general knack for recognizing and killing many types of infected or abnormal cells also can be engineered to hunt down cells with specific targets on them to treat cancer, researchers at The University of Texas MD Anderson Cancer Center report in the journal Leukemia.

The team’s preclinical research shows that natural killer cells derived from donated umbilical cords can be modified to seek and destroy some types of leukemia and lymphoma. Genetic engineering also boosts their persistence and embeds a suicide gene that allows the modified cells to be shut down if they cause a severe inflammatory response.

A first-in-human phase I/II clinical trial of these cord-blood-derived, chimeric antigen receptor-equipped natural killer cells opened at MD Anderson in June for patients with relapsed or resistant chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), or non-Hodgkin lymphoma. All are cancers of the B cells, another white blood cell involved in immune response.

“Natural killer cells are the immune system’s most potent killers, but they are short-lived and cancers manage to evade a patient’s own NK cells to progress,” said Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation and Cellular Therapy.

“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer — potentially for months instead of two or three weeks — are designed to address these challenges,” Rezvani said.

Moon Shots Program funds project

The clinical trial is funded by MD Anderson’s Moon Shots Program™, designed to more rapidly develop life-saving advances based on scientific discoveries.

The chimeric antigen receptor (CAR), so-called because it’s added to the cells, targets CD19, a surface protein found on B cells.

In cell lines and mouse models of lymphoma and CLL, CD19-targeted NK cells killed cancer cells and extended survival of animals compared to simply giving NK cells alone. Addition of IL-15 to the CD19 receptor was crucial for the longer persistence and enhanced activity of the NK cells against tumor cells.

NK cells are a different breed of killer from their more famous immune system cousins, the T cells. Both are white blood cells, but T cells are highly specialized hunters that look for invaders or abnormal cells that bear a specific antigen target, kill them and then remember the antigen target forever.

Natural killers have an array of inhibitory and activating receptors that work together to allow them to detect a wider variety of infected, stressed or abnormal cells.

“By adding the CD19 CAR, we’re also turning them into guided missiles,” said Elizabeth Shpall, M.D., professor of Stem Cell Transplantation and Cell Therapy.

Using a viral vector, the researchers transduce NK cells taken from cord blood with the CD19 CAR, the IL-15 gene, and an inducible caspase-9-based suicide gene.

Cell line tests found the engineered NK cells to be more efficient killers of lymphoma and CLL cells, compared to unmodified NK cells, indicating the engineered cells’ killing was not related to non-specific natural killer cell cytotoxicity.

Another experiment showed the engineered cord blood NK cells killed CLL cells much more efficiently than NK cells taken from CLL patients and engineered, highlighting the need to transplant CAR-engineered NK cells from healthy cord blood rather than use a patient’s own cells.

Suicide gene to counter cytokine release syndrome

Mouse model lymphoma experiments using a single infusion of low dose NK cells resulted in prolongation of survival. At a higher, double dose, none of the mice treated with the CD19/IL-15 NK cells died of lymphoma, with half surviving for 100 days and beyond. All mice treated with other types of NK cells died by day 41.

A proportion of mice treated with the higher dose of engineered NK cells died of cytokine release syndrome, a severe inflammatory response that also occurs in people treated with CAR T cells.

To counteract this toxicity, the researchers incorporated a suicide gene (iC9) that can be activated to kill the NK cells by treatment with a small-molecule dimerizer. This combination worked to swiftly reduce the engineered NK cells in the mouse model.

Subsequent safety experiments were conducted in preparation for the clinical trial. Rezvani, the principal investigator of the clinical trial, says the protocol calls for vigilance for signs of cytokine release syndrome, treatment with steroids and tocilizumab for low-grade CRS with AP1903 added to activate the suicide gene for grade 3 or 4 CRS.

NK CARs available off the shelf

T cells modified with chimeric antigen receptors against CD19 have shown efficacy in clinical trials. In these therapies, a patient’s own T cells are modified, expanded, and given back to the patient, a process that takes weeks. Finding a matched donor for T cells would be a challenge, but would be necessary because unmatched T cells could attack the recipient’s normal tissue – graft vs. host disease.

Rezvani and Shpall have given patients cord-blood derived NK cells in a variety of clinical trials and found that they do not cause graft vs. host disease, therefore don’t have to be matched. NK cells can be an off-the-shelf product, prepared in advance with the necessary receptor and given promptly to patients.

“CAR NK cells are scalable in a way that CAR T cells are not,” Rezvani noted.

A strength of T cells is the development of memory cells that persist and repeatedly attack cells bearing the specific antigen that return. NK cells do not seem to have a memory function, but Rezvani says the experience of the longer-lived mice, which are now more than a year old, raises the possibility that a prolonged NK cell attack will suffice.

Shpall, Rezvani and colleagues are developing cord blood NK CARs for other targets in a variety of blood cancers and solid tumors.

MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.

Shpall founded and directs MD Anderson’s Cord Blood Bank, originally established to provide umbilical cord blood stem cells for patients who need them but cannot get a precise donor match. Donated by mothers who deliver babies at seven Houston hospitals and two others from California and Michigan, the bank now has 26,000 cords stored. MD Anderson researchers pioneered the extraction and expansion of NK cells from umbilical cords.

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Altered virus may expand patient recruitment in human gene therapy trials

For many patients, participating in gene therapy clinical trials isn’t an option because their immune system recognizes and fights the helpful virus used for treatment. Now, University of Florida Health and University of North Carolina researchers have found a solution that may allow it to evade the body’s normal immune response.

The discovery, published May 29 in the Proceedings of the National Academy of Sciences, is a crucial step in averting the immune response that prevents many people from taking part in clinical trials for various disorders, said Mavis Agbandje-McKenna, Ph.D., a professor in the University of Florida College of Medicine department of biochemistry and molecular biology and director of the Center for Structural Biology.

During gene therapy, engineered viruses are used to deliver new genes to a patient’s cells. While the recombinant adeno-associated virus, or AAV, is effective at delivering its genetic cargo, prior natural exposure to AAV results in antibodies in some people. As many as 70 percent of patients have pre-existing immunity that makes them ineligible for gene therapy clinical trials, Agbandje-McKenna said.

The findings provide a road map for designing virus strains that can evade neutralizing antibodies, said Aravind Asokan, Ph.D., an associate professor in the department of genetics at the University of North Carolina, who led the study. At UF Health, the structural “footprints” where pre-existing antibodies interact with the virus were identified using cryo-electron microscope resources provided by the UF College of Medicine and the UF Office of Research’s Division of Sponsored Programs. The UNC researchers then evolved new viral protein shells. Using serum from mice, rhesus monkeys and humans, the researchers showed that the redesigned virus can slip past the immune system.

“This is the blueprint for producing AAV strains that could help more patients become eligible for human gene therapy. Now we know how to do it,” Agbandje-McKenna said.

While the findings prove that one variation of AAV can be evolved, further study in preclinical models is needed before the approach can be tested in humans. Next, the immune profile of one particularly promising virus variant will need to be evaluated in a larger number of human serum samples, and dose-finding studies are needed in certain animal models. Researchers may also need to study whether the same virus-manipulating technique can be used in a broader range of gene therapy viruses, Agbandje-McKenna said.

Although human gene therapy remains an emerging field and has yet to reach patients on a wide scale, researchers elsewhere have used AAV therapy to successfully treat hemophilia, a blood-clotting disorder, in a small trial. It has also been or is now being studied as a way to treat hereditary blindness, certain immune deficiencies, neurological and metabolic disorders, and certain cancers.

The latest findings are the result of more than 10 years of studying the interactions between viruses and antibodies and a long-standing collaboration with Asokan, who heads the synthetic virology group at the UNC Gene Therapy Center, according to Agbandje-McKenna.

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Clinical trial shows experimental drug’s ability to knock down pancreatic cancer’s defense

By adding an experimental drug to a standard chemotherapy regimen, a subset of patients with metastatic pancreatic cancer had a significantly longer period before the cancer progressed as compared with those who received the standard treatment, according to a Phase 2 clinical trial led by an investigator at Fred Hutchinson Cancer Research Center.

The randomized, controlled trial found that when the experimental therapy was given to participants whose tumors had a lot of the drug’s target molecule, they had four months more of progression-free survival than participants in the control group who only had the chemo.

For anyone not familiar with the rapid deadliness of pancreatic cancer, it may be hard to see the significance of the few additional months before disease progression. But time is precious for patients with this cancer: Only about 8 percent of all pancreatic cancer patients survive five years after diagnosis.

Dr. Sunil Hingorani, the faculty member at Fred Hutch who led the trial, is scheduled to present the findings at 10:24 a.m., June 4, at the American Society of Clinical Oncology annual meeting in Chicago. ASCO abstract number 4008.

Hingorani said that the results reassure him that it was the right move to advance the drug, called PEGPH20, into the worldwide Phase 3 trial that opened last year.

“We still haven’t fully proven anything yet, strictly speaking, but I think [this strategy] is very rational,” he said. “Let me put it this way: I think it would be irresponsible not to finish the global Phase 3 trial as the most rigorous test of this hypothesis. I think we’re obligated now to answer the question.”

Hingorani consults for Halozyme, the PEGPH20 drugmaker and the sponsor of these trials. The company began this year to provide funding through Fred Hutch to support Hingorani’s research on the drug.

Hingorani’s earlier research led him to the drug because he believed it could address a challenge posed by many pancreatic cancers: The tumors have very high internal pressures that collapse local blood vessels and prevent cancer-killing drugs from getting in. PEGPH20 reduces those pressures so chemotherapies circulating in the blood can penetrate tumors.

The experimental drug, which was created from the blueprint of a naturally occurring enzyme, breaks down a molecule called hyaluronic acid that is produced in bulk by many pancreatic cancers.

Hyaluronic acid, or HA, is naturally found in the human body; it readily binds water to create a gel fluid, making it an excellent shock-absorber in your knees, for example. But in pancreatic tumors, it spells trouble. As the gel fluid builds up, it raises the tumor’s internal pressure, squeezing local blood vessels shut. Patients whose tumors have a lot of HA also tend to have a poor prognosis.

Hingorani and his team first conducted studies in mice that showed how PEGPH20, in combination with chemo, permanently reduced the amount of pressure-boosting HA inside the mouse tumors. It caused the tumors to shrink and increased the mice’s survival time.

In the Phase 2 trial, patients with late-stage pancreatic cancer were randomly assigned to receive a standard-of-care, first-line combination chemotherapy either with or without PEGPH20. When the results of all 234 evaluable patients on Halo 202 were grouped together, the apparent benefit of PEGPH20 was small ? a matter of just a couple extra weeks of progression-free survival.

“If this was all the potential that this strategy represented, I wouldn’t pursue this [research further],” Hingorani said. “That’s not enough for me.”

But a stark difference emerged when the results were divided up by how much of the drug’s target, HA, patients’ tumors contained: In the subset of 80 patients whose tumors had high levels of HA, adding PEGPH20 to chemo resulted in an average of 9.2 months before disease progression; with chemo alone, this timespan was just 5.2 months.

Hingorani also reported that the unexpected, elevated risk of blood clots associated with PEGPH20 ? which resulted in a temporary halt of the trial in 2014 ? equalized between the patients receiving PEGPH20 and those in the control group, and dropped overall, after the study was restarted, due to the addition of a blood thinner to all patients’ regimens.

“These are the real take-home messages to me, namely, the progression-free survival in target-rich [high-HA] patients and the ability to give the enzyme safely,” Hingorani said.

Because the Phase 2 trial results suggest that the benefit of the experimental drug is restricted to the patients with high levels of HA in their tumors, only patients with such tumors qualify for the new Phase 3 trial. And the Phase 3 trial is designed to offer a more stringent test of the benefits of the new drug than its predecessor: Aimed at advancing the drug toward potential FDA approval, the trial’s goal is to determine whether PEGPH20 actually increases participants’ lifespans, not just their time to disease progression. (It’s possible a treatment could achieve the latter without impacting the former.)

The investigators’ exploratory analysis of the Phase 2 trial data suggested that the experimental drug boosted the lifespans of patients with high-HA tumors to an average of nearly a year after diagnosis ? which, if shown definitively in the Phase 3 trial, could be a new benchmark for this cancer, Hingorani said.

Hingorani launched the Phase 3 trial before handing off its leadership to two other colleagues in the field, Dr. Margaret Tempero of the University of California, San Francisco and Dr. Eric Van Cutsem at the University of Leuven in Belgium. As he steps back from his leadership role on this project, Hingorani is satisfied by the solid scientific foundation the investigators have lain to justify moving forward with the development of this drug.

In light of the grim timelines associated with a pancreatic cancer diagnosis, he said, patients have no time to waste on anything less.

“Patients get one shot on goal, if that, with this cancer,” he said. “No cancer is more daunting than pancreas cancer.”

Treatment-related adverse events for trial participants included peripheral edema (63 percent of those receiving PEGPH20 vs. 26 percent for the control group), muscle spasms (56 percent vs 3 percent), neutropenia (34 percent vs 19 percent), and myalgia (26 percent vs. 7 percent).

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Immunotherapy with DNA vaccine shows promise for HPV-related head and neck cancer

A novel vaccine therapy can generate immune responses in patients with head and neck squamous cell carcinoma (HNSCCa), according to researchers at the Abramson Cancer Center of the University of Pennsylvania. The treatment specifically targets human papillomavirus (HPV), which is frequently associated with HNSCCa, to trigger the immune response. Researchers will present the results of their pilot study during the 2017 American Society of Clinical Oncology Annual Meeting in Chicago (Abstract #6073).

HNSCCa is a cancer that develops in the mucous membranes of the mouth, and throat. While smoking and tobacco use are known causes, the number of cases related to HPV infection – a sexually transmitted infection that is so common, the Centers for Disease Control says almost all sexually active adults will contract it at some point in their lifetimes – is on the rise. The CDC now estimates 70 percent of all throat cancers in the United States are HPV-related. Sixty percent are caused by the subtype known as HPV 16/18.

“This is the subtype we target with this new therapy, and we’re the only site in the country to demonstrate immune activation with this DNA based immunotherapeutic vaccine for HPV 16/18 associated head and neck cancer,” said the study’s lead author Charu Aggarwal, MD, MPH, an assistant professor of Hematology Oncology in the Perelman School of Medicine at the University of Pennsylvania.

The vaccine is delivered as an injection of antigens – which leads the immune system to start producing antibodies and activate immune cells. At the time of injection, physicians use a special device to deliver a pulse of electricity to the area, which stimulates the muscles and speeds the intake of the antigens. Aggarwal noted that this study represents a multidisciplinary approach involving the lab and the clinic.

“This is truly bench-to-bedside and shows the value of translational medicine within an academic medical center,” Aggarwal said.

Penn researchers treated 22 patients with the vaccine. All of the patients had already received therapy that was intended to be curative – either surgery or chemotherapy and radiation. When doctors followed up an average of 16 months later, 18 of those patients showed elevated T cell activity that was specific to HPV 16/18. All of the patients in the study are still alive, and none reported any serious side effects.

“The data show the therapy is targeted and specific, but also safe and well-tolerated,” Aggarwal said.

Because of the positive activity, Aggarwal says the next step is to try this therapy in patients with metastatic disease. A multi-site trial will open soon that combines the vaccine with PD-L1 inhibitors, which target a protein that weakens the body’s immune response by suppressing T-cell production.

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Forge Therapeutics Raises $15M Series A Financing to Develop First Novel Gram-Negative Antibiotic in Decades

Forge Therapeutics, Inc., a biotechnology company discovering first-in-class antibiotics using a breakthrough drug discovery platform, announced today the completion of a $15M Series A financing. The round is led by MagnaSci Ventures, with participation from Evotec AG, Alexandria Venture Investments, MP Healthcare Venture Management, Red Apple Group, and WS Investments. Forge has used its enabling technology to identify a novel LpxC inhibitor effective against multi-drug resistant bacteria ‘superbugs,’ and the funding will support the program into clinical studies.

“This financing is an important step forward to solving the ‘superbug’ epidemic, an urgent global health issue in desperate need of innovation. We’ve been impressed with the strength of the Forge team, their technologies and their commitment to innovating the antibiotic space,” said Brian T. Dorsey, Founding Partner at MagnaSci Ventures. “With our investment and resources, we look forward to working together on developing the first novel antibiotic against Gram-negative bacteria in decades.” In connection with the Series A financing, Mr. Dorsey will be joining Forge’s Board of Directors.

“We are pleased to have such quality investors join us in our pursuit to eradicate deadly ‘superbug’ infections with novel antibiotics stemming from our robust drug discovery engine,” said Zachary A. Zimmerman, Ph.D., CEO of Forge. “The proceeds from this financing, coupled with the non-dilutive monies received from government agencies CARB-X and NIH/NIAID, will advance our LpxC inhibitor into clinical studies.”

With its proprietary chemistry approach, Forge develops small molecule inhibitors targeting metalloenzymes.  Forge’s lead effort is focused on LpxC, a zinc metalloenzyme found only in Gram-negative bacteria and which is essential for bacteria to grow. Forge has discovered novel small molecule inhibitors of LpxC that are potent in vitro, efficacious in vivo, and effective against drug resistant Gram-negative bacteria ‘superbugs.’

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AACR: Phase II Trial Shows Rice Bran Promotes Microbiome Diversity, Slows Growth of Colorectal Cancer Cells

Today at the American Association for Cancer Research (AACR) Annual Meeting 2017, University of Colorado Cancer Center researchers at Colorado State University present results of a phase II clinical trial of 29 people exploring the effects of adding rice bran or navy beans to the diets of colorectal cancer survivors. After the 4-week randomized-controlled trial during which people added rice bran, navy bean powder or neither, both the rice bran and navy bean groups showed increased dietary fiber, iron, zinc, thiamin, niacin, vitamin B6, folate, and alpha-tocopherol. The rice bran group also showed increased microbiome richness and diversity. When researchers treated colorectal cancer cells with stool extracts from these groups, they saw reduced cell growth from the groups that had increased rice bran and navy bean consumption.

Previous work shows the ability of these diets to decrease colorectal cancer risk in animal models. The current trial confirms that people can eat enough bean- and rice bran-enhanced foods to promote gut health at levels shown to prevent colorectal cancer in animals.

Guidelines from the American Institute for Cancer Research recommend reducing the risk of cancer by eating more vegetables, fruits, whole grains and legumes, such as beans. Ryan has established from these studies that eating a half-cup of beans and 30 grams of rice bran per day is enough to see changes in small molecules that can confer protection against colorectal cancer.

“The simple message is, ‘Food is medicine,’ and we are looking at how to simplify that and make it apply to our everyday lives,” says study co-author Regina Brown, MD, assistant professor at the CU School of Medicine and oncologist for CUHealth.

Brown is long-time collaborator of CU Cancer Center investigator and CSU assistant professor, Elizabeth Ryan, PhD. The Ryan Lab in the CSU College of Veterinary Medicine and Biomedical Sciences studies the potential power of navy beans and rice bran to promote digestive health and to prevent metabolic alterations in obesity, heart disease and certain cancers.

“The evidence is there in animals and we can now study this in people. The question is, what are we doing to achieve adequate levels of intake of these foods?” Ryan said. “It’s not enough to say ‘I eat them once in a while.’ That’s not going to work, particularly if you are at higher risk. You have to meet a dose, just like you need a dose of a certain drug, you need to reach intake levels and consume increased amounts of these foods, and that’s where people, including me, are challenged. Not everyone wants to open up a can of beans and eat them every day.”

The two met about 10 years ago, when Ryan was a researcher in CSU professor Henry Thompson’s Cancer Prevention Lab, and Brown was practicing medicine in Fort Collins and caring for her mother, who had uterine cancer.

“It was kind of a novel partnership and had we not dug in our heels it could have died, but I told Elizabeth, ‘Your work is so interesting and so valuable. We have to take this translational research from the benchtop to the clinic.’ I guarantee, nine out of 10 of my patients, the first thing they ask is about their diet,” Brown said.

The study’s lead author is Erica Borresen, Ryan’s research associate and study coordinator, who worked with colorectal cancer survivors to make sure they ate their beans and rice bran provided in meals and snacks, and that they filled out their food logs and gastrointestinal health questionnaires. It was sometimes intimate and awkward, but so is getting a colonoscopy and being treated for colorectal cancer.

“Our participants donated their time and effort, and I want to make sure they understand they are appreciated,” said Borresen, who earned her Master of Public Health at the Colorado School of Public Health, and plans to become a physician’s assistant. “I came to realize I love the patient interaction – that’s one of my favorite parts about coordinating our studies.”

The next phase of Ryan’s research examines effects of the cooked navy bean powder and rice bran on the colon tissue of people who have already had colorectal cancer and are at high risk for recurrence.

“I really feel that there’s hope in this being a practical solution to improve gut health and specifically colorectal cancer prevention,” says Ryan.

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First in Human’ Trial Defines Safe Dosage for Small Molecule Drug ONC201 for Solid Cancer Tumors

Research from Rutgers Cancer Institute of New Jersey examines oral drug that targets cancer cells and spares healthy tissue

A ‘first in human’ clinical trial examining the small molecule drug ONC201 in cancer patients with advanced solid tumors shows that this investigational drug is well tolerated at the recommended phase II dose. That’s according to Rutgers Cancer Institute of New Jersey investigators and colleagues whose research also showed early signs of clinical benefit in patients with advanced prostate and endometrial cancers. The work appears in the ‘OnlineFirst’ section of Clinical Cancer Research (DOI: 10.1158/1078-0432.CCR-16-2658).

At focus is the investigational drug ONC201 that targets a dopamine receptor, a member of the G protein-coupled receptor superfamily residing on the surface of cancer cells, to cause their destruction. ONC201 is the first of a new family of therapeutic compounds called imipridones. Previous research on the study drug conducted by Rutgers Cancer Institute and Oncoceutics, Inc. – which is also supporting this trial – suggests that ONC201 may be capable of turning off proteins that maintain tumor growth and and may help kill cancer cells while sparing normal ones. Pre-clinical study demonstrated ONC201 was effective in laboratory models against a number of solid tumors including colon cancer, brain cancer, triple-negative breast cancer and non-small cell lung cancer.

In this phase I dose-escalation study, 10 patients over age 18 with advanced solid tumors that were resistant to standard therapies were enrolled through Rutgers Cancer Institute between January and July 2015. Participants received a starting dose of 125mg of the study drug, which was taken orally via capsule every 21 days (one cycle). The dosage for this cohort was increased incrementally up to a maximum dose of 625mg, which is five-fold above the dose that was effective in laboratory models. An additional 18 patients were enrolled in an expansion phase between August 2015 and February 2016 and treated at the recommended phase II dose of 625mg in order to collect additional safety, pharmacokinetic and pharmacodynamic information.

There were no drug-related adverse events over Grade 1 in either the dose escalation phase or the expansion phase. The few low grade events that were recorded (nausea, fever) were resolved quickly, note the authors. While the study achieved the aim of identifying the recommended phase II dose of the drug, findings also showed tumor regression in patients with metastatic disease. Results also demonstrated prolonged stable disease following more than nine cycles (27 weeks) of treatment – particularly in prostate and endometrial cancer patients that had lymph node, bone and lung lesion involvement. Out of the 28 participants, 10 completed at least four cycles of treatment with two patients receiving at least nine cycles. The authors note while a 90-year old prostate cancer patient saw his primary tumor and metastatic bone lesion shrink by about 25 percent after taking two 625mg doses of ONC201, a 72-year old patient with advanced clear cell endometrial cancer had a mixed response after two doses, with multiple nodes decreasing by more than 30 percent but experiencing the development of new nodes.

“By exploring a novel agent that targets the cancer but leaves non-cancerous tissue untouched, we have an opportunity to not only provide a new treatment option for patients who have exhausted standard forms of therapy without the typical toxicities associated with anticancer treatment, but to also offer them a therapeutic that may result in a better quality of life since healthy cells are not impacted,” notes Rutgers Cancer Institute medical oncologist Mark Stein, MD, who is an associate professor of medicine at Rutgers Robert Wood Johnson Medical School and lead investigator of the work. “While meaningful to confirm the safety profile of this dosage for ONC201, it is noteworthy that our findings also showed some evidence of clinical benefit to some patients.”

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Pivotal Trial Begins for Breast Fibroadenoma Using Focused Ultrasound

Patients with benign breast tumors may be eligible for a new focused ultrasound–based investigational treatment as part of a pivotal, multi-center clinical study. The trial began last month at the University of Virginia (UVA) Medical Center.

David Brenin, MD, Associate Professor of Surgery and Chief of Breast Surgery at UVA, is the Principal Investigator for the trial. He recently completed a 20-patient pilot study to test the safety and efficacy of the device, Theraclion’s EchoPulse system. Now, in this single arm prospective study, the procedure will be performed in 100 patients at several sites worldwide, including UVA, Montefiore Medical Center, Columbia Presbyterian, Bellevue Hospital Center in New York, and others. As these new sites begin treating, the list of locations will be updated on our website and on clinicaltrials.gov.

“The patient selection criteria have been updated since the pilot study,” says Dr. Brenin. “The new parameters for the size of the fibroadenoma and the range of symptoms should allow us to include more patients. Furthermore, our experience and improvements to the device have allowed us to decrease the overall treatment time.”

EchoPulse is designed to non-invasively ablate benign breast tumors using ultrasound-guided focused ultrasound treatment. Although it is not yet approved by the US Food and Drug Administration, the system received the CE Mark in Europe five years ago, where it is also used to treat breast fibroadenomas and treat thyroid nodules and is also under investigation for other conditions.

“If this multi-center trial is successful, we will seek regulatory approval in the US,” says Theraclion’s Chief Medical Officer, Michel Nuta, MD. “Approval by the FDA would allow many more women to receive precise treatment of breast fibroadenomas non-invasively and on an outpatient basis, enabling them to return to their daily lives almost immediately.”

Patients who are interested in this study at the University of Virginia (IRB# 19437) should contact Research Coordinator Katie Rea via phone (434) 243-0315 or email uvastac@virginia.edu. More information for patients and referring physicians can also be found on the UVA website.

Dr. Brenin plans to present the initial data from the pilot study at the 18th Annual Meeting of the American Society of Breast Surgeons in Las Vegas in April 2017.

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Georgetown Announces Phase II Clinical Trial of Nilotinib for Parkinson’s Disease

Georgetown University Medical Center (GUMC) today announces the launch of a phase II clinical trial to study the safety of the cancer drug nilotinib and its effects on clinical outcomes and biomarkers in people with Parkinson’s disease.

GUMC is recruiting volunteers for the study in collaboration with its clinical partner, MedStar Georgetown University Hospital.

The clinical trial is a phase II, randomized, double-blind, placebo-controlled study designed to evaluate the safety and tolerability of low doses of nilotinib, the efficacy on disease biomarkers, and clinical outcomes in people with mid-stage Parkinson’s disease. Fernando Pagan, MD, medical director of the GUMC Translational Neurotherapeutics Program and director of the Movement Disorders Clinic at MedStar Georgetown University Hospital will serve as principal investigator on this study.

As part of the year-long random ascending dose trial, a third of the participants will receive 150mg of nilotinib, another third will receive 300mg of nilotinib and the final third will receive a placebo (inactive drug). Clinical outcomes will be assessed at six and 12 months and compared to assessments at the start of the trial. A one-year open-label extension trial, in which all participants will be randomized to 150mg or 300mg nilotinib, is also planned upon completion of the placebo-controlled trial to evaluate nilotinib’s long-term effects.

The clinical trial follows a proof of concept study conducted at Georgetown (published July 11, 2016 in the Journal of Parkinson’s Disease) providing molecular evidence that nilotinib significantly increased brain dopamine (the chemical lost as a result of neuronal destruction) and reduced toxic proteins linked to disease progression in Parkinson’s disease or dementia with Lewy bodies. Twelve participants were enrolled in the initial study; one patient withdrew due to an adverse event. Researchers say the drug appeared to be safe and well tolerated in the remaining 11 participants who completed the study.

“The early proof of concept study conducted in 2015 and published in 2016 provided encouraging results, but we won’t know the exact effects of nilotinib on Parkinson’s disease until larger trials like this new one are complete,” says Pagan.

“I am pleased to offer this study to my patients, which demonstrates the importance of teaming Parkinson’s care with academic research. Only through clinical trials will we be able to move the field forward so that we can offer better treatments to our patients in the future,” he adds.

Nilotinib is approved by the U.S. Food and Drug Administration at much higher doses for the treatment of chronic myeloid leukemia (CML). In 2016, the U.S. Food and Drug Administration reviewed Georgetown’s investigational new drug application (IND) for the nilotinib study in Parkinson’s disease and informed GUMC investigators that the trial could proceed.

The Parkinson’s study and the recently announced Alzheimer’s clinical trial with nilotinib build on research from the GUMC Translational Neurotherapeutics Program led by Charbel Moussa, MB, PhD. He and his colleagues are examining tyrosine kinase inhibitors, like nilotinib, in the treatment of neurodegenerative diseases. Tyrosine kinases appear to play a role in neurodegeneration, protein clearance and inflammation. (Moussa is an inventor on a US patent owned by Georgetown University and on other pending US and foreign patent applications for use of nilotinib and other tyrosine kinase inhibitors for the treatment of neurodegenerative diseases).

The Parkinson’s study is funded by the generous support of donors. Novartis, the maker of nilotinib, is providing nilotinib and matching placebo free of cost to Georgetown University for all participants while on the study.

More information can be found at ClinicalTrials.gov. Patients and families can sign up to receive more information about the Parkinson’s study and other Georgetown neurodegenerative clinical trials.

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Two New Trials for Pediatric Brain Cancer Open at UTHealth/Children’s Memorial Hermann

Two new clinical trials for pediatric brain cancer have begun at The University of Texas Health Science Center at Houston (UTHealth) and Children’s Memorial Hermann Hospital.

The pilot trials, approved by the U.S. Food and Drug Administration, both focus on the administration of chemotherapy agents directly into the fourth ventricle of the brain, the most common site for pediatric brain tumors and one that is difficult to access surgically.

“Administering chemotherapy directly to the site of the tumor can enable very high drug levels at the site of active disease while decreasing the likelihood of systemic toxicity,” said David Sandberg, M.D., the Dr. Marnie Rose Professor in Pediatric Neurosurgery at McGovern Medical School at UTHealth, who pioneered the procedure. “Current treatment options can have serious side effects, and we need to do better. Radiation therapy can be harmful to the developing brain and chemotherapy in the high levels needed to cross the blood-brain barrier can cause many side effects as well as damage to organs throughout a child’s body.”

Both trials are designed to target brain tumors that develop in the posterior fossa portion of the brain that includes the cerebellum, brain stem and fourth ventricle.

One trial builds on Sandberg’s previous research that investigated the infusion of methotrexate for pediatric brain tumors. Results of the research, published in October 2015 in the Journal of Neuro-Oncology, showed that some patients with recurrent medulloblastoma experienced a beneficial anti-tumor effect. The new study will look at combining methotrexate with another chemotherapy agent, etoposide, for infusion into the fourth ventricle for medulloblastoma, the most common malignant brain tumor in children. Children with other tumors such as atypical teratoid rhabdoid tumor (ATRT) are also eligible.

The second trial focuses on a different chemotherapy agent for a type of brain tumor called recurrent posterior fossa ependymoma. Ependymomas form from ependymal cells that line the ventricles and passageways in the brain and spinal cord, according to the National Cancer Institute.

The chemotherapy agent, 5-azacytidine (5-AZA), is infused directly into the fourth ventricle. The agent has never been injected into a human brain before but has been shown to be promising in treating ependymomas in the laboratory. No systemic chemotherapy will be given to clinical trial participants.

Both studies are open to patients age 1 to 21.

The procedures will be done at Children’s Memorial Hermann Hospital, where Sandberg is director of Pediatric Neurosurgery. He is also director of Pediatric Neurosurgery at Memorial Hermann Mischer Neuroscience Institute at the Texas Medical Center. Sandberg is a professor in both the Department of Pediatric Surgery and the Vivian L. Smith Department of Neurosurgery at McGovern Medical School.

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University Hospitals Rainbow Babies & Children’s Hospital Opens First Stem Cell Study in Patients with Cystic Fibrosis

Study is first step toward goal of developing therapy to quell CF’s lung inflammation

A 39-year-old man with cystic fibrosis (CF) made history by becoming the first person to receive human adult stem cells in a new research study that researchers hope will someday lead to the development of a therapy to reduce the inflammation and infection caused by CF.

The pioneering subject in the study is Bob Held from Alliance, Ohio, who on Jan. 26 received an infusion of cells called allogeneic human mesenchymal stem cells (hMSC), adult stem cells collected from the bone marrow of healthy volunteers. Mr. Held was diagnosed with CF when he was 16 months old.

Currently, there is no cure for CF, and life expectancy for patients who survive into adulthood is approximately 41 years of age.

“It was a very exciting day for us with the very first participant in the first stem cell trial for cystic fibrosis,” said James Chmiel, MD, the principal investigator of the study at University Hospitals Rainbow Babies & Children’s Hospital.

The Phase 1 trial will assess the safety and tolerability of hMSCs in adult patients with CF.

“This is an early phase trial, and the most important thing is to ensure safety,” said Dr. Chmiel. “This study consists of a single infusion of stem cells. We will follow the study participants for a year to make sure it’s safe. Before applying any therapy on a broad basis, we want to make sure that it’s safe.”

While the goal of the study is safety, Dr. Chmiel hopes this is a first step towards the ultimate goal of developing a therapy to reduce lung inflammation and infection, resulting in longer and healthier lives for people with CF.

“While there’s been a tremendous increase in survival for people with CF from when I entered the field in the 1990s, that’s still not good enough,” said Dr. Chmiel, Director of the Cystic Fibrosis Therapeutics Development Center at UH Rainbow Babies & Children’s Hospital and Professor of Pediatrics at Case Western Reserve University School of Medicine. “While we’ve made great progress, we still have a long way to go.”
The stem cells that Mr. Held received were collected from the bone marrow of a healthy adult volunteer. UH is a national leader in the use of stem cell therapy with hMSCs. Researchers from UH, along with the CWRU School of Medicine, discovered hMSCs. The hMSCs possess many properties that are ideal for the treatment of inflammatory and degenerative diseases, and they possess natural abilities to detect changes in their environment, such as inflammation. The hope is that hMSCs can reduce the inflammation in the lungs caused by CF.

CF’s main effect is on the lungs. They fill with a sticky mucus as a reaction – really an over-reaction – by the body’s immune system to bacteria. The lungs are the source for much of the illness and shortened lifespan seen in CF.

“One of the issues in CF is that people with the disease get bacterial infections in their lungs, and these bacteria incite a vigorous and excessive inflammatory response,” explained Dr. Chmiel. “It’s actually the body’s inflammatory response that damages the lungs. The inflammatory response tries to eliminate the bacteria, but it’s not successful. Instead, the inflammatory system releases molecules that damage the individual’s own airways. The lung disease causes much of the illness and is responsible for the majority of the mortality of the disease.”

The stem cells are donated by healthy adult volunteers who go through a rigorous screening process. The stem cells are cultured in the UH stem cell facility. Volunteers with CF who are in the study receive an infusion through an IV.
“Once in the patient’s body, the stem cell tracks to the area where there’s a significant amount of inflammation, and they take up residence there. The stem cells then respond to the environment, and hopefully reverse some of the abnormalities,” said Dr. Chmiel. “We hope in future studies to demonstrate that the stem cells reduce the infection and inflammation and return the lungs to a more normal state.”

“This therapy aims to turn down the inflammatory response, not eliminate it because we still have to keep the bacteria in check. We want to reduce inflammation and the subsequent lung damage caused by inflammation without allowing the bacteria to proliferate,” said Dr. Chmiel.

A total of 15 clinically stable adults with CF will be enrolled in the study. Support for the study is from the Cystic Fibrosis Foundation.

The patient, Mr. Held, considers himself fortunate to be close to 40 with CF. When he was growing up, he said he’d miss 50 days of school each year because of the disease. Every day, he needs to breathe in aerosols for about two hours in the morning and 1-1/2 hours before bed to keep his lungs functioning. While he hasn’t been sick from the illness since his late teens, he does check himself into the hospital a couple of times a year for precautionary measures and to prevent himself from “getting into a valley” with CF.

His late wife, Michelle, died of CF seven years ago. They had met when they were kids, but didn’t get married until 2012. She died from the disease suddenly 28 days after they married.

“My only regret is that I didn’t ask her out sooner,” said Mr. Held.
He is participating in the study to carry on Michelle’s legacy, and “I am hoping the future generations of CF patients can get better treatments and that eventually a cure will be found for them,” he said.

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Georgetown Clinical Trial of Nilotinib in Alzheimer’s Disease Begins

 A clinical trial to examine the effect of nilotinib on clinical outcomes and biomarkers in people with mild to moderate Alzheimer’s disease has opened at Georgetown University Medical Center (GUMC).

The clinical trial is a phase II, randomized, double blinded, placebo-controlled study to evaluate the impact of low doses of the cancer drug(Tasigna®). GUMC is conducting the study with its clinical partner, MedStar Georgetown University Hospital.

The rationale for using nilotinib is based on laboratory and clinical research conducted by the Georgetown Translational Neurotherapeutics Program (TNP). Nilotinib appears to aid in the clearance of accumulated beta-amyloid (Abeta) plaques and Tau tangles in the brain. Both are hallmarks of Alzheimer’s disease. Nilotinib appears to penetrate the blood-brain barrier and turn on the “garbage disposal” machinery inside neurons (a process known as autophagy) to clear the Tau, Abeta and other toxic proteins.

“In a 2015 proof of concept study at Georgetown, patients with Parkinson’s disease or dementia with Lewy bodies were treated with nilotinib. As my colleagues reported, those who completed the study had a reversal in disease progression, observed both clinically and in key biomarkers—the same biomarkers seen in Alzheimer’s,” explains Scott Turner, MD, PhD, medical co-director of the TNP, who will serve as principal investigator for the study. “But even before the Parkinson’s study, research in the laboratory strongly supported studying this drug in people with Alzheimer’s. The promising results of the Parkinson’s study give an even stronger rationale.”

“When used in higher doses for chronic myelogenous leukemia (CML), nilotinib forces cancer cells into autophagy or cell death. The dose used in CML treatment is significantly higher than what we will use in our Alzheimer’s study,” says Charbel Moussa, MB, PhD, scientific and clinical research director for the Translational Neurotherapeutics Program. “When used in smaller doses once a day, as in this study, it appears nilotinib turns on autophagy for about four to eight hours—long enough to clean out the cells without causing cell death. Toxic proteins that build up again then appear to be cleared when the drug is given again the next day.”

Moussa initially conducted the preclinical research that led to the discovery of nilotinib for the potential treatment of neurodegenerative diseases.

Moussa is an inventor on a US patent owned by Georgetown University and on other pending US and foreign patent applications for use of nilotinib and other tyrosine kinase inhibitors for the treatment of neurodegenerative diseases.

The Alzheimer’s Drug Discovery Foundation is supporting this clinical trial through a $2.1 million grant to Turner. The study has also received private philanthropic support.

Turner conducts additional clinical research supported by funding to Georgetown University from Lilly, Biogen, Merck, Acadia, and Toyama as well as the National Institutes of Health and Department of Defense.

To learn more about this clinical trial, please click here. To learn about other Alzheimer’s clinical studies, please visit the Georgetown Memory Disorders Program website.

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Patients with Severe Chronic Rhinosinusitis Show Improvement with Verapamil Treatment

A small clinical trial at Massachusetts Eye and Ear found that patients with chronic rhinosinusitis (CRS) with nasal polyps improved with Verapamil therapy

A clinical trial studying the use of Verapamil (a drug currently in use for cardiovascular disease and cluster headache) in alleviating chronic rhinosinusitis (CRS) with nasal polyps revealed significant improvement in the symptoms of this subset of patients. It is the first study of its kind to explore treatment for CRS by inhibiting P-glycoprotein, a protein pump within the nasal lining that Mass. Eye and Ear researchers previously identified as a mechanism for these severe cases of CRS marked by the presence of nasal polyps. The clinical trial results, published online today in the Journal of Allergy and Clinical Immunology: In Practice, suggest that Verapamil represents a promising novel therapy for the treatment of CRS with nasal polyps.

“Recently, we became aware that some of the inflammation in CRS with nasal polyps is generated by the nasal lining itself, when a particular protein pump (P-glycoprotein) is overexpressed and leads to the hyper-secretion of inflammatory cytokines,” said senior author Benjamin S. Bleier, M.D., a sinus surgeon at Mass. Eye and Ear and an assistant professor of otolaryngology at Harvard Medical School. “Verapamil is a first-generation inhibitor that is well-established in blocking P-glycoprotein. In some patients with CRS with nasal polyps, we saw dramatic improvement in their symptom scores.”

One of the more prevalent chronic illnesses in the United States, CRS has been known to cause significant quality of life detriments to affected patients, who often cannot breathe or sleep easily due to obstructed nasal and sinus passages. The presence of nasal polyps represents a particularly severe presentation of the disease. Current treatment strategies (most often long-term steroid use) are plagued by difficult side effects and fail to target an underlying source of the disease.

Motivated by their previous finding of the presence of P-glycoprotein overexpression in the nasal lining of patients with CRS with nasal polyps, the study authors conducted a randomized, double-blind, placebo-controlled clinical trial studying the use of low-dose Verapamil in 18 patients with CRS with nasal polyps. An analysis of these patients demonstrated improved outcomes for those in the Verapamil group in relation to those in the placebo group. However, the researchers also observed that the treatment effect was significantly limited among patients with higher body mass indices. Future studies are being planned to determine if a higher dose of Verapamil may be needed to be therapeutic for some patients.

“Chronic rhinosinusitis with nasal polyps is among our most challenging diagnoses to treat, because these patients essentially have chronic, lifelong inflammation that needs chronic, lifelong treatment,” said Dr. Bleier. “We observed no significant side effects at the doses we used, and we are very encouraged by the results of this first step toward a more targeted therapy for our patients.”

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Leukemia Drug Combo Is Encouraging in Early Phase I Clinical Trial

In a small study, 67 percent of leukemia patients treated with combination of thioguanine and decitabine responded to treatment

Researchers from Columbia University Medical Center and NewYork-Presbyterian reported that 8 out of 12 patients with relapsed and/or chemotherapy refractory acute myeloid leukemia (AML) or other blood cancers responded to a regimen including the chemotherapy drugs thioguanine and decitabine. Results from this small phase I study were reported at the American Society of Hematology’s annual conference.

“Outcomes are typically poor for older patients with advanced blood cancers, and new therapies are desperately needed to help patients with these cancers achieve remission,” said Mark Frattini, MD, PhD, associate professor of medicine at Columbia University Medical Center (CUMC) and blood cancer specialist at NewYork-Presbyterian. “While our study was small, the response we saw in this phase I, dose-escalating trial was encouraging.”

Previously, Frattini and colleagues had used a proprietary chemosensitivity screening assay to demonstrate that combining thioguanine and decitabine—chemotherapy drugs that are commonly used as single agents to treat patients with AML—restored therapeutic efficacy in leukemia cells from patients with relapsed and/or refractory disease.

In this study, the researchers tested the efficacy of the combination therapy in 12 older patients (median age of 67 years) with relapsed or chemotherapy refractory AML or chronic myelomonocytic leukemia, including 6 patients whose disease progressed after being treated previously with decitabine as a single agent. Of these, 11 patients completed the first treatment cycle, and 6 completed a second cycle, with a median of 3 rounds of treatment. Eight of the 11 evaluable patients responded to the combination therapy, including 6 who achieved a complete remission (5 in complete remission with incomplete count recovery). In addition, all of the patients who had progressed after prior treatment with decitabine alone responded to the combination therapy, demonstrating that the combination could overcome disease resistance to decitabine. Chemosensitivity assay results, obtained before treatment, accurately predicted each patient’s response to the combination therapy.

After treatment with the combination therapy, 4 of the responders went on to have a stem cell transplant.

“The goal of chemotherapy for patients with relapsed and/or refractory AML and other blood cancers is to achieve a remission that enables them to undergo a potentially curative stem cell transplant,” said Dr. Frattini. “With our phase I results, we have shown that this combination therapy can get some patients—including those who failed to respond to or progressed after previous chemotherapy treatment with a single agent such as decitabine—to that point. The next challenge for hematologic oncologists is to reduce morbidity and mortality associated with stem cell transplantation.”

After the study, 2 of the patients who had a stem cell transplant died from transplant-related toxicity, and another relapsed. One patient has remained in remission for more than 2 years.

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After One Dose of Gene Therapy, Hemophilia B Patients Maintain Near-Normal Levels of Clotting Factor

At ASH Meeting, CHOP Hematologist Leads Clinical Trial in Which All Subjects Safely Maintain Factor IX Expression that Curtails Disabling Bleeding

Researchers are reporting the highest and most sustained levels to date of an essential blood-clotting factor IX in patients with the inherited bleeding disorder hemophilia B. After receiving a single dose of an experimental gene therapy in a clinical trial, patients with hemophilia produced near-normal levels of clotting factor IX, allowing them to stop clotting factor infusions and to pursue normal activities of daily life without disabling bleeding episodes.

Lindsey A. George, MD, a hematologist at Children’s Hospital of Philadelphia (CHOP)is the lead investigator of the phase 1/2 clinical trial sponsored by Spark Therapeutics, Inc. and Pfizer, Inc. The American Society of Hematology (ASH) today highlighted updated findings from that trial in a press conference during its annual meeting in San Diego. George will present those study results tomorrow at an ASH plenary scientific session.

Katherine High, MD, a senior author of the study and Spark Therapeutics’s president and chief scientific officer, described the updated interim trial data at today’s press conference. The clinical trial of nine adult hemophilia B patients, aged 18 to 52 years, used a single dose of a gene therapy product engineered to enter patients’ liver cells and direct the production of the blood clotting factor that they lack.

George notes, “Our goal in this trial was to evaluate the safety of the gene therapy product and secondarily, to determine if we could achieve levels of factor IX that could decrease bleeding events in patients.” She added, “These patients have a severe or moderate level of hemophilia, with baseline clotting factor level less than or equal to 2 percent of levels in healthy people. In current treatment, patients with hemophilia give themselves intravenous doses of factor IX up to a couple times a week. While generally effective, factor levels fluctuate, and patients may suffer painful, disabling joint bleeds when their clotting factor levels drop. Such a regimen requires significant planning of daily activities.”

In the current trial, said George, the patients maintained factor levels of approximately 30 percent, enough to lift them out of the severe category. “At these new levels, hemophilia patients do not typically need to self-treat with factor to avoid bleeding events,” she said, adding, “This represents a potential dramatic improvement in their quality of life and a shift in the way we think about treating hemophilia.” A factor level of 30 percent is near-normal, she added, and patients would be expected to experience bleeding only in the event of major trauma or surgery.

One subject self-infused two days after receiving the gene therapy vector. Beyond this, no patients had any bleeding events or required factor for any reason. With significant reduction in bleeding events and factor use, six of the first seven patients reported increased physical activity and all reported improved quality of life. Two additional patients received the gene therapy product too recently to determine quality-of-life measures.

Previous hemophilia gene therapy trials have been frustrated by an immune response to the gene therapy product that limited the success of the therapy. In the current trial, two patients experienced an immune response to the gene therapy that did not result in safety concerns, and were treated with steroids. The patients are still undergoing treatment but have maintained factor IX activity without bleeding.

George reported that she is cautiously optimistic, acknowledging that this trial is a small study, with a short follow-up period as yet. However, as the researchers continue to monitor patients in the current trial, next steps will be to discuss with the U.S. Food and Drug Administration the outlines of a larger, phase 3 clinical trial. No gene therapies for any genetic diseases have yet been approved for clinical use in the U.S.

Formerly a research leader at CHOP, High pursued groundbreaking preclinical investigations in hemophilia B gene therapy and provided scientific expertise to previous gene therapy trials in hemophilia and other genetic disorders at CHOP before moving to Spark Therapeutics, which was spun off from CHOP in 2013. CHOP maintains a financial interest in the company.

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Study Finds Arthritis Drug Significantly Effective in Treating Crohn’s Disease

Researchers at University of California San Diego School of Medicine have shown that ustekinumab, a human antibody used to treat arthritis, significantly induces response and remission in patients with moderate to severe Crohn’s disease. Results of the clinical trial will appear in the November 16 issue of the New England Journal of Medicine.

“A high percentage of the patients in the study who had not responded to conventional therapies were in clinical remission after only a single dose of intravenous ustekinumab,” said William J. Sandborn, MD, professor of medicine at UC San Diego School of Medicine and director of the Inflammatory Bowel Disease Center at UC San Diego Health. “Finding effective new treatment options for this patient population is critical because Crohn’s disease can dramatically impact a person’s quality of life. Patients suffering from this disease may go to the bathroom up to 20 times a day and experience abdominal pain, ulcers and a reduced appetite.”

Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract that affects approximately 700,000 people in the United States. It can affect any part of the GI tract but it is more commonly found at the end of the small intestine (the ileum) where it joins the beginning of the large intestine (or colon). Crohn’s disease is usually treated with glucocorticoids, immunosuppressants, tumor necrosis factor (TNF) antagonists or integrin inhibitors.

“The drawbacks of these therapies include an increased risk of infection and cancer, and limited efficacy,” said Sandborn. “Ustekinumab has not been associated with an increased risk of serious adverse events.”

The rates of remission response in the randomized study at week six among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving a placebo. The study also found subcutaneous (injected) ustekinumab every 8 to 12 weeks maintained remission in patients.

“This study indicates that ustekinumab may have a long duration of action, a likelihood that may become better understood in future trials,” said Sandborn. “Our current findings offer hope for those suffering from this debilitating gastrointestinal tract disease.”

The Inflammatory Bowel Disease (IBD) Center at UC San Diego Health is dedicated to diagnosing and treating people with IBD from around the world. The center’s leadership in IBD medical research means patient access to clinical trials for the newest therapies and advanced surgical techniques for the treatment of this challenging condition. Care is provided by a multidisciplinary team of specialists in gastroenterology, endoscopy, oncology, surgery, transplantation and radiology.

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Smallest-Reported Artificial Virus Could Help Advance Gene Therapy

Gene therapy is a kind of experimental treatment that is designed to fix faulty genetic material and help a patient fight off or recover from a disease. Now scientists have engineered the smallest-reported virus-like shell that can self-assemble. It could someday carry potentially therapeutic DNA or RNA and transfer it to human cells. The report appears in the Journal of the American Chemical Society.

The story of gene therapy is fraught with much hype and high-profile failures. But, hype and failures aside, it remains a promising route to treat a range of ailments, from rare genetic diseases to common conditions such as diabetes. Clinical trials to test various gene therapy treatments are underway. One possible approach is to copy the way viruses behave. When they infect people, viruses inject their genetic material into human cells. Artificial viruses have been engineered to mimic this step, but they tend to clump or are not uniform in size, which can hinder their effectiveness. Max Ryadnov and colleagues wanted to address these issues.

Rather than using full proteins, the researchers used short peptide sequences designed to assemble into tiny gene carriers, which are smaller than previously reported synthetic viruses and even naturally occurring viruses. Lab testing showed that their artificial viral shells were uniform in size and didn’t clump. The particles could encase DNA or RNA and transfer the genetic material to human cells without harm. Depending on the introduced material, the recipient cells then either expressed a new protein or stopped expressing their own protein.