Wistar scientists develop novel immunotherapy technology for prostate cancer

A study led by scientists at The Wistar Institute describes a novel immunotherapeutic strategy for the treatment of cancer based on the use of synthetic DNA to directly encode protective antibodies against a cancer specific protein. This is the first application of the new technology, called DNA-encoded monoclonal antibody (DMAb), for cancer immunotherapy. The study was published online in Cancer Immunology, Immunotherapy.

Prostate cancer is the second most common cancer in men worldwide. Traditional treatments are invasive and can impair the quality of life of patients, underscoring the need for alternative therapeutic strategies, including immunotherapy. One of the immunotherapeutic approaches that has been explored thus far relies on the use of monoclonal antibodies that specifically target a protein present on the surface of prostate cancer cells called prostate specific membrane antigen (PSMA) to elicit an anti-tumor immune response and control the cancer. Although promising, this strategy is limited by the production cost required to make these therapeutic antibodies. Additionally, multiple infusions are often required to achieve efficacy.

Wistar researchers devised a novel DNA-based approach in which an engineered DNA plasmid is constructed and used to deliver the instructions to make the desired anti-PSMA antibody so that the therapy can be generated in the patient’s body in a sustained manner. This research has important implications for the use of DNA-encoded monoclonal antibody technology as a platform for delivering the next generation of immunotherapies for cancer and many human diseases.

“This is an important demonstration of the possibilities opened up for immunotherapy by DMAb technology to direct in vivo production of antibodies of major relevance to human cancer,” said David B. Weiner, Ph.D., executive vice president of The Wistar Institute, director of The Wistar Institute Vaccine & Immunotherapy Center, W.W. Smith Charitable Trust Professor in Cancer Research, and senior author of the study. “There is a great need for such new approaches for prostate disease as well as many other cancers. As recent data suggest, PSMA is an important cancer antigen expressed on many human prostate, bladder, renal as well as ovarian cancers, so additional study of the possible benefits of this therapy are important.”

The new technology was tested in mice for the ability to generate antibodies in their blood stream that would target human PSMA as well as target PSMA-positive tumors. Results showed that antibodies were able to bind to the cancer cells and recruited specific immune cells called natural killer cells, resulting in shrinkage of the tumor, significantly improving survival.

“Our data provide proof of concept that DMAb engineered DNA plasmids can be successfully used to target important cancers,” said Kar Muthumani, M.Sc., Ph.D., assistant professor in the Translational Tumor Immunology Program at Wistar, member of the Vaccine & Immunotherapy Center and lead author of the study. “The unique features of our synthetic DNA-based system make it a promising novel approach for cancer therapy, alone or in combination with other treatments.”

Experimental HIV vaccine regimen is well-tolerated, elicits immune responses

Results from an early-stage clinical trial called APPROACH show that an investigational HIV vaccine regimen was well-tolerated and generated immune responses against HIV in healthy adults. The APPROACH findings, as well as results expected in late 2017 from another early-stage clinical trial called TRAVERSE, will form the basis of the decision whether to move forward with a larger trial in southern Africa to evaluate vaccine safety and efficacy among women at risk of acquiring HIV.

The APPROACH results will be presented July 24 at the 9th International AIDS Society Conference on HIV Science in Paris.

The experimental vaccine regimens evaluated in APPROACH are based on “mosaic” vaccines designed to induce immunological responses against a wide variety of HIV subtypes responsible for HIV infections globally. Different HIV subtypes, or clades, predominate in various geographic regions around the world. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, funded pre-clinical development of these vaccines. Together with other partners, NIAID supported the APPROACH trial, which is sponsored by Janssen Vaccines & Prevention B.V., part of the Janssen Pharmaceutical Companies of Johnson & Johnson. The manufacture and clinical development of the mosaic vaccines are led by Janssen.

“A safe and effective HIV vaccine would be a powerful tool to reduce new HIV infections worldwide and help bring about a durable end to the HIV/AIDS pandemic,” said NIAID Director Anthony S. Fauci, M.D. “By exploring multiple promising avenues of vaccine development research, we expand our opportunities to achieve these goals.”

APPROACH involved nearly 400 volunteers in the United States, Rwanda, Uganda, South Africa and Thailand who were randomly assigned to receive one of seven experimental vaccine regimens or a placebo. APPROACH found that different mosaic vaccine regimens were well-tolerated and capable of generating anti-HIV immune responses in healthy, HIV-negative adults. Notably, the vaccine regimen that was most protective in pre-clinical studies in animals elicited among the greatest immune responses in the study participants. However, further research will be needed because the ability to elicit anti-HIV immune responses does not necessarily indicate that a candidate vaccine regimen can prevent HIV acquisition.

According to the researchers, the findings from APPROACH, as well as from animal studies, support further evaluation of a lead candidate regimen in a clinical trial to assess its safety and efficacy. Plans for such a clinical trial to be conducted in southern Africa are in development, with projected enrollment of 2,600 healthy, HIV-negative women. Should the larger trial move forward, it is expected to begin enrollment in late 2017 or early 2018.

In APPROACH, study participants received four vaccinations over 48 weeks: two doses of an initial, or “prime,” vaccine, followed by two doses of a booster vaccine. The experimental regimens all incorporated the same vaccine components in the prime vaccination, known as Ad26.Mos.HIV. The vaccine uses a strain of common-cold virus (adenovirus serotype 26, or Ad26), engineered so that it does not cause illness, as a vector to deliver three mosaic antigens created from genes from many HIV variants. The booster vaccination included various combinations of the Ad26.Mos.HIV components or a different mosaic component, called MVA-Mosaic, and/or two different doses of clade C HIV gp140 envelope protein containing an aluminum adjuvant to boost immune responses.

The Ad26-based mosaic vaccines were initially developed by the laboratory of NIAID grantee Dan H. Barouch, M.D., Ph.D., and Janssen. In pre-clinical studies, regimens incorporating these mosaic vaccines protected monkeys against infection with an HIV-like virus called simian human immunodeficiency virus (SHIV). The most effective prime-boost regimen reduced the risk of infection per exposure to SHIV by 94 percent and resulted in 66 percent complete protection after six exposures. Researchers identified and characterized the vaccine-induced immune responses that correlated with this protection.

“The promising, early-stage results from the APPROACH study support further evaluation of these candidate vaccines to assess their ability to protect those at risk of acquiring HIV,” said Dr. Barouch, a principal investigator for APPROACH. He also is director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston and professor of medicine at Harvard Medical School.

Following the third vaccination, most APPROACH participants had developed antibody and cellular immune responses against HIV. The different boost vaccines altered the magnitude and character of these immune responses, with the regimen that showed greatest protection in monkey studies also eliciting among the greatest immune responses in humans. The anti-HIV immune responses increased after the fourth vaccination.

The researchers conclude that further evaluation of this approach would use a regimen comprising two Ad26 mosaic primes and two boosts with Ad26 mosaic and clade C gp140. The ongoing TRAVERSE trial is comparing Ad26-based regimens containing three mosaic antigens (trivalent) with Ad26-based regimens containing four mosaic antigens (tetravalent). Results from TRAVERSE are expected in late 2017.

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.

Researchers take an important step toward an HIV vaccine

Vaccines are an essential tool for preventing and treating serious infectious diseases such as polio, chicken pox and measles. But so far it has not been possible to develop vaccines capable of contributing to the treatment and prevention of chronic infectious diseases such as HIV and hepatitis C.

This new research paves the way for vaccines that, as opposed to conventional methods, boosting the parts of the immune system attacking the viral genes, which are the least active during the infection. This prolongs the resistance of the immune system to the virus.

Traditional vaccines typically cause a strong stimulation of the parts of the immune system, that are most responsive to the specific virus. But the reaction to the vaccine and the infection is often so intense that the immune system ‘loses momentum’ and consequently is not able to completely eliminate the virus. Researchers have therefore designed a vaccine which boosts the cells of the immune system responsible for the less exposed parts of the virus. As a result, the cells are able to distribute the ‘work load’ and retain the defense against the virus attack for a longer period of time. This gives the immune system time to build a more efficient defense, which may then defeat the remaining of the virus.

“We’re presenting an entirely new vaccine solution. Our vaccine supports the work of the immune system in developing an effective combating mechanism against the virus, rather than immediately combating the toughest parts of the virus. In combination with other vaccines, this approach can prove to have a highly efficient effect,” says Research Team Leader and Associate Professor Peter Holst of the Department of Immunology and Microbiology.

In 2008, the research team decided to develop a new vaccine strategy, which generates so-called strong immune responses against weak immunostimulatory parts of viruses. Research initially focused on experiments on mice and later on monkeys.

Now, the results of the research team show, that this technology can control the SIV virus infection (simian immunodefiency virus) in monkeys. SIV is a chronic infectious disease and a highly realistic representation of HIV. The results are an important step toward developing a vaccine against HIV and other chronic infections.

“The next phase of our work is to build virus control in all infected animals and later in humans. We’re convinced that it’s possible to identify further improvements in our experiments and thus achieve a well-functioning vaccine, initially against HIV, but also against other chronic infections,” says Peter Holst.

GeoVax to Collaborate with Georgia State on Development of Hepatitis B Therapeutic Vaccine

The Georgia State University Research Foundation has entered into a research collaboration agreement with GeoVax Labs, Inc., a Georgia-based biotechnology company developing human vaccines, to advance development of a therapeutic vaccine for treatment of chronic Hepatitis B infections.

The Centers for Disease Control and Prevention estimates between 700,000 to 1.4 million people in the United States have chronic Hepatitis B virus infections, with an estimated 20,000 new infections every year.

The research collaboration will include the design, construction and characterization of multiple vaccine candidates by combining the preS VLP technology from Georgia State and GeoVax’s MVA-VLP vaccine platform. Unique VLP design and functional assays developed by Dr. Ming Luo, professor in the Department of Chemistry at Georgia State, and performed in collaboration with Peking University Shenzhen Graduate School, will provide key information on vaccine effectiveness.

“My team’s efforts continue to unveil the molecular mechanism of immune responses to HBV infection and we are excited to partner with GeoVax to further the development of a Hepatitis B therapeutic vaccine,” said Dr. Luo. “Globally, chronic Hepatitis B affects more than 240 million people and contributes to nearly 686,000 deaths worldwide each year. By joining forces with GeoVax, we will apply our highly complementary sets of expertise in an effort to address the problem.”

The vaccine will be based upon generating the preS VLP using the GeoVax’s novel MVA-VLP vector platform, which has been proven safe in multiple human clinical trials of the company’s preventive HIV vaccine. This platform is also being used to develop preventive vaccines against Zika virus and hemorrhagic fever viruses, such as Ebola, Sudan, Marburg and Lassa.

Moffitt Cancer Center Researchers Report Promising Clinical Activity and Minimal Toxicities for HER2-Targeted Dendritic Cell Vaccines in Early-Stage Breast Cancer Patients

HER2-Targeted Dendritic Cell Vaccines Stimulate Immune Responses and Regression of HER2-Expressing Early-Stage Breast Tumors

Deregulation and inhibition of the immune system contributes to cancer development. Many therapeutic strategies aim to restimulate the immune system to recognize cancer cells and target them for destruction. Researchers from Moffitt Cancer Center report that a dendritic cell vaccine that targets the HER2 protein on breast cancer cells is safe and effectively stimulates the immune system leading to regression of early-stage breast cancer.

The HER2 protein is overexpressed in 20-25% of all breast cancer tumors and is associated with aggressive disease and poor prognosis. Moffitt researchers have previously shown that immune cells are less able to recognize and target cancer cells that express HER2 as breast cancer progresses into a more advanced and invasive stage. This suggests that strategies that can restimulate the immune system to recognize and target HER2 early during cancer development may be effective treatment options.

The Moffitt researchers previously developed a vaccine that helps the immune system recognize the HER2 protein on breast cancer cells. Their approach involves creating the vaccine from immune cells called dendritic cells that are harvested from each individual patient to create a personalized vaccine.

In order to determine if the HER2-dendritic cell vaccine is safe and effective, the Moffitt researchers performed a clinical trial in 54 women who have HER2-expressing early-stage breast cancer. The dendritic cell vaccines were prepared by isolating dendritic cells from each patients’ blood and exposing them to fragments of the HER2 protein. Patients were injected with a dose of their personal dendritic cell vaccine once a week for 6 weeks into either a lymph node, the breast tumor, or into both sites.

The researchers report that the dendritic cell vaccines were well-tolerated and patients only experienced low-grade toxicities. The most common adverse events were fatigue, injection site reactions, and chills. They also show that the vaccine was able to stimulate an immune response in the majority of the patients. Approximately 80% of evaluable patients had a detectable immune response in their peripheral blood and/or in their sentinel lymph node wherein their cancer is most likely to spread to first. Importantly, the immune responses among the patients were similar, regardless of the route of vaccine administration.

The Moffitt researchers assessed the effectiveness of the vaccine by determining the percentage of patients who had detectable disease within surgical specimens after resection. The absence of disease is termed a pathological complete response (pCR). They report that 13 patients achieved a pCR and patients who had early non-invasive disease called ductal carcinoma in situ (DCIS) achieved a higher rate of pCR than patients who had early-stage invasive disease. Interestingly, patients who achieved a pCR had a higher immune response within their local sentinel lymph nodes.

“These results suggest that vaccines are more effective in DCIS, thereby warranting further evaluation in DCIS or other minimal disease settings, and the local regional sentinel lymph node may serve as a more meaningful immunologic endpoint,” said Brian J. Czerniecki, MD, PhD, Chair of the Department of Breast Oncology at Moffitt Cancer Center.

Engineers design a new weapon against bacteria

Over the past few decades, many bacteria have become resistant to existing antibiotics, and few new drugs have emerged. A recent study from a U.K. commission on antimicrobial resistance estimated that by 2050, antibiotic-resistant bacterial infections will kill 10 million people per year, if no new drugs are developed.

To help rebuild the arsenal against infectious diseases, many scientists are turning toward naturally occurring proteins known as antimicrobial peptides, which can kill not only bacteria but other microbes such as viruses and fungi. A team of researchers at MIT, the University of Brasilia, and the University of British Columbia has now engineered an antimicrobial peptide that can destroy many types of bacteria, including some that are resistant to most antibiotics.

“One of our main goals is to provide solutions to try to combat antibiotic resistance,” says MIT postdoc Cesar de la Fuente. “This peptide is exciting in the sense that it provides a new alternative for treating these infections, which are predicted to kill more people annually than any other cause of death in our society, including cancer.”

De la Fuente is the corresponding author of the new study, and one of its lead authors along with Osmar Silva, a postdoc at the University of Brasilia, and Evan Haney, a postdoc at the University of British Columbia. Timothy Lu, an MIT associate professor of electrical engineering and computer science, and of biological engineering, is also an author of the paper, which appears in the Nov. 2 issue of Scientific Reports.

Improving on nature

Antimicrobial peptides, produced by all living organisms as part of their immune defenses, kill microbes in several different ways. First, they poke holes in the invaders’ cell membranes. Once inside, they can disrupt several cellular targets, including DNA, RNA, and proteins.

These peptides also have another critical ability that sets them apart from traditional antibiotics: They can recruit the host’s immune system, summoning cells called leukocytes that secrete chemicals that help kill the invading microbes.

Scientists have been working for several years to try to adapt these peptides as alternatives to antibiotics, as bacteria become resistant to existing drugs. Naturally occurring peptides can be composed of 20 different amino acids, so there is a great deal of possible variation in their sequences.

“You can tailor their sequences in such a way that you can tune them for specific functions,” de la Fuente says. “We have the computational power to try to generate therapeutics that can make it to the clinic and have an impact on society.”

In this study, the researchers began with a naturally occurring antimicrobial peptide called clavanin-A, which was originally isolated from a marine animal known as a tunicate. The original form of the peptide kills many types of bacteria, but the researchers decided to try to engineer it to make it even more effective.

Antimicrobial peptides have a positively charged region that allows them to poke through bacterial cell membranes, and a hydrophobic stretch that enables interaction with and translocation into membranes. The researchers decided to add a sequence of five amino acids that would make the peptides even more hydrophobic, in hopes that it would improve their killing ability.

This new peptide, which they called clavanin-MO, was very potent against many bacterial strains. In tests in mice, the researchers found that it could kill strains of Escherichia coli and Staphylococcus aureus that are resistant to most antibiotics.

Suppressing sepsis

Another key advantage of these peptides is that while they recruit immune cells to combat the infection, they also suppress the overactive inflammatory response that can cause sepsis, a life threatening condition.

“In this single molecule, you have a synthetic peptide that can kill microbes — both susceptible and drug-resistant — and at the same time can act as an anti-inflammatory mediator and enhance protective immunity,” de la Fuente says.

The researchers also found that these peptides can destroy certain biofilms, which are thin layers of bacterial cells that form on surfaces. That raises the possibility of using them to treat infections caused by biofilms, such as the Pseudomonas aeruginosa infections that often affect the lungs of cystic fibrosis patients. Or, they could be embedded into surfaces such as tabletops to make them resistant to microbial growth.

Other possible applications for these peptides include antimicrobial coatings for catheters, or ointments that could be used to treat skin infections caused by Staphylococcus aureus or other bacteria.

If these peptides are developed for therapeutic use, the researchers anticipate that they could be used either in stand-alone therapy or together with traditional antibiotics, which would make it more difficult for bacteria to evolve drug resistance. The researchers are now investigating what makes the engineered peptides more effective than the naturally occurring ones, with hopes of making them even better.

Neurodevelopmental Model Of Zika May Provide Rapid Answers

A newly published study from researchers working in collaboration with the Regenerative Bioscience Center at the University of Georgia demonstrates fetal death and brain damage in early chick embryos similar to microcephaly—a rare birth defect linked to the Zika virus, now alarming health experts worldwide.

The team, led by Forrest Goodfellow, a graduate student in the UGA College of Agricultural and Environmental Sciences, developed a neurodevelopmental chick model that could mimic the effects of Zika on the first trimester. Historically, chick embryos have been extensively used as a model for human biology.

Early last spring, Goodfellow began inoculating chick embryos with a virus strain originally sourced from the Zika outbreak epicenter.

“We wanted a complete animal model, closely to that of a human, which would recapitulate the microcephaly phenotype,” said Goodfellow, who recently presented the findings at the Southern Translational Education and Research (STaR) Conference.

The RBC team, which included Melinda Brindley, an assistant professor of virology in the College of Veterinary Medicine, and Qun Zhao, associate professor of physics in the Franklin College of Arts and Sciences, suggests that the chick embryo provides a useful model to study the effects of Zika, in part because of its significant similarity to human fetal neurodevelopment and rapid embryonic process.

“Now we can look quickly, at greater numbers, to take a closer look at a multitude of different strains and possibly identify the critical window of susceptibility for Zika virus-induced birth defects,” said Brindley. “With this approach, we can continue to further design and test therapeutic efficacy.”
The challenge today is unpredictable disease outbreaks and how to ramp up process and production of therapeutic antibodies in preparation. Having an active pathogen threat like Zika that can jump across continents reinforces the need for therapeutic innovation.

Early stage chick embryos are readily available and low in cost, Goodfellow explained. Development within the egg (in ovo) provides an environment that can be easily accessed by high-speed automation. Poultry automation in the Southeast is impressive, and the industry is now using robotic technology, Goodfellow said.

“With egg injection automation and embryo viability technology, we could test tens of thousands of potential therapeutic compounds in a single day,” he said.
Since 2011, under the mentorship of Steven Stice, a Georgia Research Alliance Eminent Scholar and director of the Regenerative Bioscience Center, Goodfellow has worked extensively with eggs and chickens. In a previous project with Stice and Zhao, the team developed a unique approach of marrying stem cell biology and MRI to track and label neural stem cells.

“We knew we could look at the brain structure, shape and size with MRI, but what we captured was evidence that the infection caused MRI-visible damage, and the total brain volume was substantially smaller,” said Stice, faculty lead and principal investigator of the study. “From this finding, our data provides a rationale for targeting future therapeutic compounds in treating early-stage microcephaly to stop or slow the progress of the disease.”

Q&A with Heat Biologics’ Founder and CEO Jeffrey Wolf on T Cell Stimulating Cancer Immunotherapies

Immuno-oncology, a field of fast advancing science that activates a patient’s own immune system against cancer, holds great promise.  A number of companies in the field are developing treatment platforms, many of which are patient-specific (autologous) and therefore costly. Heat BiologicsImPACT (Immune Pan-Antigen Cytotoxic Therapy) is fully allogeneic, off-the-shelf and cost-efficient, offering the potential to enhance patients’ natural immune response against certain cancers.

ImPACT therapy transforms living allogeneic cells into “antigen pumps” that continuously secrete antigens in the patient’s body to robustly stimulate the immune system against the targeted cancer. While ImPACT therapy may be applicable to a wide range of cancers, Heat is currently conducting multiple clinical trials in two indications.

Currently in Phase 2, HS-410 represents the first potential new immunotherapy to treat non-muscle invasive bladder cancer (NMIBC) and is being evaluated as both a monotherapy as well as in combination with standard of care.  Heat’s second product candidate, HS-110, is being evaluated in a Phase 1b trial in combination with nivolumab (Opdivo®), a Bristol-Myers Squibb PD-1 checkpoint inhibitor, for the treatment of non-small cell lung cancer (NSCLC).

Data from its Phase 2 NMIBC trial, as well as data from its NSCLC trial, will be reported in the fourth quarter of this year.

The Bio Connection recently spoke with Heat Biologics’ Founder and CEO Jeffrey Wolf about the Company’s ImPACT immuno-oncology platform.

Q: There is a lot of excitement around the potential for T cell therapies. Can you tell us more about your proprietary ImPACT platform and its advantages compared to others on the market and in development?

Wolf: Our ImPACT platform technology is an off-the-shelf therapeutic anti-cancer vaccine that stimulates a uniquely potent CD8+ T cell response against a broad array of cancer tumor antigens. We feel it potentially provides the broadest and most robust immune system stimulation against targeted cancers, and the intradermal injection has proven to be a very user-friendly route of administration.

Another main advantage really comes with the ease-of-use and cost benefits relative to being allogeneic and not patient-specific.  Autologous or “personalized” therapeutic vaccine approaches require the extraction of blood or tumor tissue from each patient and the creation of an individualized treatment; whereas, our product candidates are fully allogenic, do not require extraction of individual patient materials or custom manufacturing.  As such, our product candidates can be mass-produced and readily available for immediate patient use, offering logistical, manufacturing and other cost benefits compared to one-off, patient-specific approaches.

Using our ImPACT platform technology, we have developed two product candidates and have reported favorable safety profiles to-date, shown clinical evidence of mechanism of action and early signals of efficacy.  Furthermore, we have begun work on our second generation platform technology, ComPACT, which combines a T cell priming vaccine and T cell co-stimulator in a single product, offering the potential benefits of combination immunotherapy in a single drug without the need for multiple independent biologic products.  Again, this is in line with developing ease-of-use and cost efficient therapies.

Q: As an off the shelf product, ImPACT can benefit from scalable low cost manufacturing relative to autologous therapies. Can you tell us how this key competitive advantage can help Heat Biologics both leading up to and following FDA approval?

Wolf: We have already begun planning our commercial production and have found that our platform technology scales well.  By the time we have our Phase 3 trials up and running, we will be in a manufacturing setup that will support commercial launch.  The major competitive advantage is that we can scale the manufacturing and stockpile bulk drug vials for patient use without having to wait for patients.  The off-the-shelf setting is advantageous to us and is well-suited to the workings of established and reputable contract manufacturing partners.

Q: It’s been 25 years since a new treatment was approved for non-muscle invasive bladder cancer.  Given the clear unmet need for a new treatment, can you tell us what size market HS-410 would address, if approved?

Wolf: Bladder cancer is the fifth most common cancer in the United States and represents one of the highest lifetime treatment costs per patient of all cancers.  Most bladder cancer patients – approximately 70 percent – are diagnosed with non-muscle invasive bladder disease, which is the population we are currently targeting.

Q: Approximately half of non-small cell lung cancer patients are not adequately served by drugs on the market today. Can you tell us how HS-110 will serve this unmet need?
Wolf:
I believe you are referring to the response rates for the new class of drugs – checkpoint inhibitors – which have been reported to only work on about 30 percent of patients or those patients who have “hot” or inflamed tumors.  By contrast, our trials are indicating that ImPACT therapies are most likely to benefit patients with non-inflamed, or “cold” tumors, by increasing the number of cancer-fighting lymphocytes that infiltrate the tumor and transform them into “hot” tumors.  In fact, we think ImPACT vaccines might be particularly effective when combined with checkpoint inhibitors, which is what our latest trial is designed to show, as we are evaluating HS-110 in combination with nivolumab to treat patients with NSCLC.  We expect to have more data on this by the end of the year.

Q: Since the ImPACT platform can address multiple cancers, which new indications would Heat Biologics pursue next and what size markets those address?

Wolf: We have been focusing our efforts on execution of our current clinical programs, and advancing our next generation platform technology, ComPACT, into the clinic.  We remain excited about the other diseases we may be able to address with these platforms, and are evaluating the best treatment landscape and markets with our physician opinion leaders.  Excitement for our platform technologies continue to build and we are enthusiastic about our products.

For more information on Heat Biologics visit www.heatbio.com (Ticker: HTBX)

New anti-cancer strategy mobilizes both innate and adaptive immune response

Though a variety of immunotherapy-based strategies are being used against cancer, they are often hindered by the inability of the immune response to enter the immunosuppressive tumor microenvironment and to effectively mount a response to cancer cells. Now, scientists from the RIKEN Center for Integrative Medical Sciences have developed a new vaccine that involves injecting cells that have been modified so that they can stimulate both an innate immune response and the more specific adaptive response, which allows the body to keep memories and attack new tumor cells as they form. In the study published in Cancer Research, they found that the vaccine made it possible for killer CD8+T-cells–important players in the immune response against cancer–to enter the tumor microenvironment and target cancerous cells.

According to Shin-ichiro Fujii, leader of the Laboratory for Immunotherapy, who led the study, “Cancer cells have different sensitivities to the innate or adaptive response, so it important to target both in order to eradicate it. We have developed a special type of modified cell, called aAVC, which we found can do this.”

The aAVC cells are not taken from the subject’s own body but are foreign cells. The cells are modified by adding a natural killer t-cell ligand, which permits them to stimulate natural killer T-cells, along with an antigen associated with a cancer. The group found that when these cells are activated, they in turn promote the maturation of dendritic cells, which act as coordinators of the innate and acquired response. Dendritic cells are key because they allow the activation of immune memory, where the body remembers and responds to a threat even years later.

To find whether it worked in actual bodies, they conducted experiments in mice with a virulent form of melanoma that also expresses a model antigen called OVA. Tests in mice showed, moreover, that aggressive tumors could be shrunken by vaccinating the animals with aAVC cells that were programmed to display OVA antigen. Following the treatment, the tumors in the treated animals were smaller and necrotic in the interior–a sign that the tumor was being attacked by the killer CD8+T-cells.

Fujii continues, “We were interesting in finding a mechanism, and were able to understand that the aAVC treatment led to the development of blood vessels in the tumors that expressed a pair of important adhesion molecules, ICAM-1 and VCAM-1, that are not normally expressed in tumors. This allowed the killer CD8+T cells to penetrate into the tumor.”

They also found that in animals that had undergone the treatment, cancer cells injected even a year later were eliminated. “This indicates,” says Fujii, “that we have successfully created an immune memory that remembers the tumor and attacks it even later.”

Looking to the future, Fujii says, “Our therapy with aAVC is promising because typical immunotherapies have to be tailor-made with the patient’s own cells. In our case we use foreign cells, so they can be made with a stable quality. Because we found that our treatment can lead to the maturation of dendritic cells, immunotherapy can move to local treatment to more systemic treatment based on immune memory.”

FDA Approves Vaccine for Cholera

In a milestone that was years in the making, a vaccine to prevent cholera, invented and developed by researchers at the University of Maryland School of Medicine’s Center for Vaccine Development, was approved today by the U.S. Food and Drug Administration (FDA).

The vaccine, Vaxchora, is the only approved vaccine in the U.S. for protection against cholera. Its licensure allows for use in people traveling to regions in which cholera is common, including travelers, humanitarian aid workers, and the military.

PaxVax, a global biotechnology company based in California, received marketing approval from the FDA for Vaxchora, a single-dose oral, live attenuated cholera vaccine that is indicated for use in adults 18 to 64 years of age. Vaxchora is the only vaccine available in the U.S. for protection against cholera and the only single-dose vaccine for cholera currently licensed anywhere in the world.

The vaccine was invented in the 1980s at Center for Vaccine Development (CVD). Since 2009, CVD researchers have worked closely with PaxVax to develop the vaccine and secure FDA licensure approval.

“This important FDA decision is the culmination of years of dedicated work by many researchers,” said Myron M. Levine, MD, DTPH, the Simon and Bessie Grollman Distinguished Professor at the University of Maryland School of Medicine (UM SOM). “For travelers to the many parts of the world where cholera transmission is occurring and poses a potential risk, this vaccine helps protect them from this disease. It is a wonderful example of how public-private partnerships can develop medicines from bench to bedside.” Dr. Levine is co-inventor of the vaccine, along with James B. Kaper, PhD, Professor and Chairman of the UM SOM Department of Microbiology and Immunology, and the senior associate dean for academic affairs at the school.

Cholera is an acute intestinal diarrheal infection acquired by ingesting contaminated food or water. Globally, cholera cases have increased steadily since 2005 and, millions of people are affected by this disease each year. Cholera can cause severe dehydration and death in less than 24 hours, if left untreated. While some cholera cases are rarely acquired in the U.S. from ingestion of uncooked seafood from the Gulf of Mexico, the vast majority of cases of domestic cholera cases occur in travelers to areas with epidemic or endemic cholera (for example, parts of Africa, Asia, or the Caribbean). A report from the U.S. Centers for Disease Control and Prevention suggests that the true number of cholera cases in the U.S. is at least 30 times higher than observed by national surveillance systems. The currently recommended intervention to prevent infection is to avoid contaminated water and food. But studies have shown that 98 percent of travelers do not follow these precautions.

Vaxchora is expected to be commercially available later this year. The FDA approval is based on results from a phase 1 safety and immunogenicity trial, a phase 3 efficacy trial, and a phase 3 trial to test manufacturing consistency. The first two of these trials were led by Wilbur H. Chen, MD, MS, associate professor of medicine at UM SOM, and chief of the CVD’s Adult Clinical Studies section. The pivotal efficacy trial, which demonstrated protection from cholera of more than 90 percent at 10 days and 80 percent at 3 months after vaccination, is the first instance the FDA has based the decision to approve a product on a human experimental challenge model. Therefore, the licensure of Vaxchora marks a significant regulatory milestone. The most common adverse reactions to Vaxchora in the clinical trials were tiredness, headache, abdominal pain, nausea/vomiting, lack of appetite and diarrhea.

Cholera is chiefly a disease of poverty, poor sanitation, and lack of access to safe drinking water, so the global health burden of cholera rests on those populations residing in vulnerable developing countries. The World Health Organization estimates the burden of cholera to be between 1.4 and 4.3 million cases per year globally. Dr. Chen said that the next steps for this cholera vaccine are to explore formulations that could be developed into successful strategies to prevent and control cholera in countries where cholera is common. These future activities would involve immunizing young children in developing countries; this group has the highest risk of dying from cholera.

“The FDA approval of a new vaccine for a disease for which there has been no vaccine available is an extremely rare event. The approval of Vaxchora is an important milestone for PaxVax and we are proud to provide the only vaccine against cholera available in the U.S.,” said Nima Farzan, chief executive officer and president of PaxVax. “We worked closely with the FDA on the development of Vaxchora and credit the agency’s priority review program for accelerating the availability of this novel vaccine. In line with our social mission, we have also begun development programs focused on bringing this vaccine to additional populations such as children and people living in countries affected by cholera.”

“This approval is an excellent example of how our researchers are entering into public-private partnerships to help further science in tangible ways,” said UM SOM Dean E. Albert Reece, MD, PhD, MBA, who is also the vice president for Medical Affairs, University of Maryland, and the John Z. and Akiko K. Bowers Distinguished Professor. “This vaccine shows once again that work by scientists here has an impact not only nationally, but globally.”