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News Article | April 24, 2017
Site: www.eurekalert.org

In lung cancer patients who were taking immunotherapy drugs targeting the PD-1 pathway, testing for CD8 T cell activation in their blood partially predicted whether their tumors would shrink. The results are scheduled for publication in PNAS. Drugs targeting PD-1 or its ligand PD-L1 re-activate "exhausted" CD8 T cells by promoting their expansion and unleashing their ability to destroy cancer cells. Researchers at Emory Vaccine Center, led by co-senior author Rafi Ahmed, PhD, have been intensively studying the cells that are revived after inhibitory signals from PD-1 are blocked. Ahmed is director of the Vaccine Center and a Georgia Research Alliance Eminent Scholar. Winship Cancer Institute investigators Rathi Pillai, MD and Suresh Ramalingam, MD, Winship's deputy director, teamed up with Alice Kamphorst, PhD and Ahmed's group to examine blood samples from 29 advanced non-small cell lung cancer patients undergoing immunotherapy treatment. The patients were being treated at Winship Cancer Institute of Emory University with drugs blocking the PD-1 pathway, known as checkpoint inhibitors (nivolumab, pembrolizumab or atezolizumab). Blood samples were obtained before starting treatment and before each new treatment cycle, which lasted two to three weeks. Most patients (70 percent) displayed an increase in the number of proliferating CD8 T cells in their blood after starting PD-1 targeted treatment -- an observable effect on the immune system. However, not all patients with an immunological response experienced a "partial clinical response", meaning that their tumors shrank by at least 30 percent. All patients with partial responses survived at least one year, while just one out of seven patients with progressive disease was reported to survive one year. Survival times for three patients were not available. An early increase in activated PD-1+ CD8 T cells appears important. 80 percent of patients with clinical benefit exhibited PD-1+ CD8 T cell responses within 4 weeks of treatment initiation. In contrast, 70 percent of patients with disease progression had either delayed or absent PD-1+ CD8 T cell responses. "We hypothesize that re-activated CD8 T cells first proliferate in the lymph nodes, then transition through the blood and migrate to the inflamed tissue," Ahmed says. "We believe some of the activated T cells in patients' blood may be on their way to the tumor." Proliferating CD8 T cells displayed high levels of PD-1, as well as other molecules that influence their activity, which may be targets for combination therapies. The Emory/Winship team recently published a paper in Science, incorporating data from this study, showing that the costimulatory molecule CD28 is required for proliferation following PD-1-targeted treatment. The current study supports a straightforward idea: if CD8 T cells appear to respond to immunotherapy, that's a good sign. "Our ability to detect proliferating T cells in the blood and correlate this with clinical benefit is exciting since this captures a real-time assessment of the immune system's response to PD-1 directed therapies and is a readily accessible test from our patients' perspective," Pillai says. While looking for activated T cells in the blood is not yet predictive enough for routine clinical use, such tests could provide timely information, says co-senior author Ramalingam. Monitoring the immune response could potentially help oncologists and patients decide, within just a few weeks of starting immunotherapy drugs, whether to continue with current treatment or combine it with something else. "We are already doing larger studies to confirm these observations and extend them to other cancers beyond lung cancer," he says. This work was funded in part by the National Institutes of Health and the T. J. Martell Foundation.


PLYMOUTH MEETING, Pa., Nov. 21, 2016 (GLOBE NEWSWIRE) -- Inovio Pharmaceuticals, Inc. (NASDAQ:INO) today announced that Dr. David B. Weiner, its co-founder, board member and chair of its scientific advisory board, has been selected as a “Top 20 Translational Researcher” for the year 2015 by the editors of Nature Biotechnology magazine. The selection is based on the number of medical innovations that led to patents a researcher was granted in a calendar year. The designation “translational researcher” refers to basic research that can move from the lab bench to become patented medicine. Dr. Weiner’s patented innovations relate to advancing the field of DNA-based immunotherapies targeting challenging infectious diseases and cancers. Over his career he holds more than 100 issued and pending U.S. patents. From 1986 until 2015, Dr. Weiner’s lab was at the University of Pennsylvania, Perelman School of Medicine. In 2016, Dr. Weiner joined The Wistar Institute, the nation’s first independent biomedical research institute, an NCI-designated Cancer Center, and an international leader in cancer, immunology and infectious disease research, as Executive Vice President, Director of its Vaccine Center and the W. W. Smith Charitable Trust Endowed Professorship in Cancer Research. Dr. J. Joseph Kim, Inovio's President and CEO, said, "This award acknowledges David’s innovation and commitment to creating tomorrow’s medicines with a revolutionary technology, DNA-based immunotherapies and vaccines, which Inovio is developing in early and late-stage clinical trials.  While I can say I am personally proud of my association with Dr. Weiner, which is now decades long, I can also say that we at Inovio as a team have tremendous respect and appreciation for his innovation and dedication to this field and congratulate him on this award.” Dr. Weiner is a world-renowned leader in immunology as well as gene vaccines and immunotherapy. In scientific circles he is known as the “father of DNA vaccines.” He has more than 350 peer-reviewed publications in scientific journals, including mainstream publications such as Scientific American, and has been designated by the Institute for Scientific Information as one of the top-cited scientists in the world. An inventor of more than 100 issued and pending U.S. patents, Dr. Weiner has received numerous honors including election as a fellow to the American Association for the Advancement of Science in 2011 and the International Society for Vaccines in 2012. He was the recipient of the NIH Director’s Transformative Research Award and received the Vaccine Industry Excellence Award for Best Academic Research Team in 2015 at the World Vaccine Congress. Dr. Weiner was honored with the prestigious Hilleman Lectureship in 2015 at the Children’s Hospital of Philadelphia Grand Rounds session and received a Stone Family Award from Abramson Cancer Center for his groundbreaking work on DNA vaccines for cancer immune therapy. David Weiner holds a Ph.D. in developmental biology from the University of Cincinnati College of Medicine, an M.S. in biology from the University of Cincinnati, and a B.S. in biology from SUNY at Stony Brook in Stony Brook, N.Y. Inovio is taking immunotherapy to the next level in the fight against cancer and infectious diseases. We are the only immunotherapy company that has reported generating T cells in vivo in high quantity that are fully functional and whose killing capacity correlates with relevant clinical outcomes with a favorable safety profile. With an expanding portfolio of immune therapies, the company is advancing a growing preclinical and clinical stage product pipeline. Partners and collaborators include MedImmune, The Wistar Institute, University of Pennsylvania, DARPA, GeneOne Life Science, Plumbline Life Sciences, Drexel University, NIH, HIV Vaccines Trial Network, National Cancer Institute, U.S. Military HIV Research Program, and Laval University. For more information, visit www.inovio.com. This press release contains certain forward-looking statements relating to our business, including our plans to develop electroporation-based drug and gene delivery technologies and DNA vaccines, our expectations regarding our research and development programs and our capital resources. Actual events or results may differ from the expectations set forth herein as a result of a number of factors, including uncertainties inherent in pre-clinical studies, clinical trials and product development programs, the availability of funding to support continuing research and studies in an effort to prove safety and efficacy of electroporation technology as a delivery mechanism or develop viable DNA vaccines, our ability to support our broad pipeline of SynCon® active immunotherapy and vaccine products, the ability of our collaborators to attain development and commercial milestones for products we license and product sales that will enable us to receive future payments and royalties, the adequacy of our capital resources, the availability or potential availability of alternative therapies or treatments for the conditions targeted by the company or its collaborators, including alternatives that may be more efficacious or cost effective than any therapy or treatment that the company and its collaborators hope to develop, issues involving product liability, issues involving patents and whether they or licenses to them will provide the company with meaningful protection from others using the covered technologies, whether such proprietary rights are enforceable or defensible or infringe or allegedly infringe on rights of others or can withstand claims of invalidity and whether the company can finance or devote other significant resources that may be necessary to prosecute, protect or defend them, the level of corporate expenditures, assessments of the company's technology by potential corporate or other partners or collaborators, capital market conditions, the impact of government healthcare proposals and other factors set forth in our Annual Report on Form 10-K for the year ended December 31, 2015, our Form 10-Q for the quarter ended September 30, 2016, and other regulatory filings from time to time. There can be no assurance that any product in Inovio's pipeline will be successfully developed or manufactured, that final results of clinical studies will be supportive of regulatory approvals required to market licensed products, or that any of the forward-looking information provided herein will be proven accurate.


Grant Provides Funding to Help Prepare New Zika Therapy for Human Trials Inovio Already in Two Human Trials for its Preventive Zika Vaccine PLYMOUTH MEETING, Pa. & PHILADELPHIA, Dec. 01, 2016 (GLOBE NEWSWIRE) -- Inovio Pharmaceuticals, Inc. (NASDAQ:INO) announced today that it has been awarded a $6.1 million sub-grant through The Wistar Institute to develop a DNA-based monoclonal antibody designed to provide a fast-acting treatment against Zika infection and its debilitating effects. The goal of this program, which is funded by a grant to The Wistar Institute from the Bill & Melinda Gates Foundation, is for the researchers to develop a Zika dMAb® therapy ready for human clinical trials in less than two years. There is no approved therapeutic or vaccine for Zika infection, presenting a major unmet medical need given that the World Health Organization estimates that more than two billion people are directly at risk for infection. Importantly, infection with the Zika virus during pregnancy can cause a pattern of birth defects including microcephaly. This new DNA-based monoclonal antibody technology has properties that best fit a response to address a Zika outbreak in that dMAb products can be designed and manufactured expediently on a large scale using common fermentation technology, are thermal-stable, and may be used as a therapy to provide more rapid protection from or limit the spread of Zika infection. Unlike vaccines, monoclonal antibody-based therapies could provide more immediate protection but do not develop long term immune memory. An ideal approach would therefore include the administration of a dMAb product for immediate protection and a DNA vaccine to train the immune system for longer-term, persistent protection against Zika infection. Inovio’s optimized DNA-based immunotherapy platform is uniquely positioned to target both immediate therapy through delivery of dMAb products as well as long-term immunity via DNA vaccination. Dr. J. Joseph Kim, President & CEO of Inovio, said, “As the leader in DNA-based immunotherapy and vaccine products, with our lead program poised to enter phase III study in the near term, we are also excited to expand our powerful technology platform to develop these new dMAb products. We thank the Gates Foundation for their confidence in the Inovio/Wistar team to develop this new type of medicine to address an emerging infectious disease like Zika. This grant marks the fourth major grant in the past couple of years backing the development of Inovio’s dMAb technology. Past grants include two from DARPA totaling over $56 million − one for dMAb products for Ebola and one for dMAb products for universal flu and antibiotic resistant bacteria − as well as one from the NIH for dMAb products for treating HIV infection.” Dr. David B. Weiner, Wistar’s Executive Vice President, Director of its Vaccine Center, and the W. W. Smith Charitable Trust Endowed Professorship in Cancer Research, is the principal investigator of this grant. Other collaborators on the award include Humabs Biomed and GeneOne Life Sciences. Dr. Weiner said, “Our team has strong expertise in DNA immunotherapy development, design and delivery technology as well as molecular immunology (The Wistar Institute) and DNA production and clinical studies including device & delivery development (Inovio Pharmaceuticals) and DNA studies in non-human primates. Our collaborative team skillset includes monoclonal antibody discovery (Humabs) and validation, and extensive experience working with in vivo infectious disease models and challenges (Wistar & Humab). Each group will perform experiments and provide essential reagents to other groups within the consortium. The team is experienced with translation from preclinical studies to the clinic.” In support of its dMAb technology, the Inovio/Wistar team reported earlier this year that its dMAb product for another emerging infectious disease, Chikungunya (CHKV), provided durable 100% protection in mice. In this study, a single intramuscular injection of a dMAb product protected mice from a lethal dose of the virus. The protection expressed by these dMAb antibodies was very rapid, with 100% survival in mice challenged with lethal disease as early as two days after dMAb product administration. In comparison, vaccine-driven protection can take weeks to months to reach peak efficacy levels, but provides better long term protection compared to a dMAb product. This published study demonstrates that an Inovio dMAb product and DNA vaccine could be used as an ideal combination to provide both rapid short-term as well as long-term protection. Inovio is the only organization to report such results in any disease using a DNA-based monoclonal antibody, with published preclinical data in dengue and HIV as well, and is also developing dMAb products for treating MERS, influenza, MRSA, RSV, Ebola and cancers. Inovio is advancing two trials for its DNA-based Zika vaccine. It expects to have preliminary results by year end for its U.S./Canada study. In Puerto Rico, where the CDC estimates Zika will infect more than 25% of the population by year end, Inovio’s second study employs a placebo control design that may provide exploratory signals of vaccine efficacy. The company expects to meet with regulators next year to determine the most efficient path forward to develop its Zika vaccine and help mitigate this widespread Zika outbreak that has now expanded into the continental United States. Unlike conventional monoclonal technology, which involves constructing protein-based antibodies and manufacturing them in cell culture in a complex and costly process, Inovio’s patent-protected DNA-based monoclonal antibody technology encodes the DNA sequence for a specific monoclonal antibody in a highly optimized plasmid, which would be delivered directly into a subject’s arm using electroporation. Cells in the body would then produce the encoded monoclonal antibody molecules, with intended functional activity including high antigen-binding and neutralization capabilities against the targeted disease. Monoclonal antibodies offer the benefit of inducing a rapid onset of the immune response. Overall, Inovio’s dMAb technology may provide clear advantages over conventional monoclonal antibody technology, including faster development, easier product manufacturing, and more favorable pharmacokinetics. The current monoclonal antibody product market is well over $50 billion. Inovio is taking immunotherapy to the next level in the fight against cancer and infectious diseases. We are the only immunotherapy company that has reported generating T cells in vivo in high quantity that are fully functional and whose killing capacity correlates with relevant clinical outcomes with a favorable safety profile. With an expanding portfolio of immune therapies, the company is advancing a growing preclinical and clinical stage product pipeline. Partners and collaborators include MedImmune, The Wistar Institute, University of Pennsylvania, DARPA, GeneOne Life Science, Plumbline Life Sciences, Drexel University, NIH, HIV Vaccines Trial Network, National Cancer Institute, U.S. Military HIV Research Program, and Laval University. For more information, visit www.inovio.com. This press release contains certain forward-looking statements relating to our business, including our plans to develop electroporation-based drug and gene delivery technologies and DNA vaccines, our expectations regarding our research and development programs and our capital resources. Actual events or results may differ from the expectations set forth herein as a result of a number of factors, including uncertainties inherent in pre-clinical studies, clinical trials and product development programs, including the Zika vaccine GLS-5700, the availability of funding to support continuing research and studies in an effort to prove safety and efficacy of electroporation technology as a delivery mechanism or develop viable DNA vaccines, our ability to support our broad pipeline of SynCon® active immunotherapy and vaccine products, the ability of our collaborators to attain development and commercial milestones for products we license and product sales that will enable us to receive future payments and royalties, the adequacy of our capital resources, the availability or potential availability of alternative therapies or treatments for the conditions targeted by the company or its collaborators, including alternatives that may be more efficacious or cost effective than any therapy or treatment that the company and its collaborators hope to develop, issues involving product liability, issues involving patents and whether they or licenses to them will provide the company with meaningful protection from others using the covered technologies, whether such proprietary rights are enforceable or defensible or infringe or allegedly infringe on rights of others or can withstand claims of invalidity and whether the company can finance or devote other significant resources that may be necessary to prosecute, protect or defend them, the level of corporate expenditures, assessments of the company's technology by potential corporate or other partners or collaborators, capital market conditions, the impact of government healthcare proposals and other factors set forth in our Annual Report on Form 10-K for the year ended December 31, 2015, our Form 10-Q for the quarter ended September 30, 2016, and other regulatory filings from time to time. There can be no assurance that any product in Inovio's pipeline will be successfully developed or manufactured, that final results of clinical studies will be supportive of regulatory approvals required to market licensed products, or that any of the forward-looking information provided herein will be proven accurate.


Article published in npj Vaccines demonstrates that DNA vaccine protected 100% of animals from Zika infection after exposure to the virus PLYMOUTH MEETING, Pa., Nov. 10, 2016 (GLOBE NEWSWIRE) -- Inovio Pharmaceuticals, Inc. (NASDAQ:INO) today announced that Inovio and its collaborators have published results in Nature Partner Journals (npj) Vaccines demonstrating that its Zika DNA vaccine (GLS-5700) protected animals from infection, brain damage and death. In this study 100% of GLS-5700 vaccinated animals were protected from Zika infection after exposure to the virus. In addition, vaccinated mice were protected from degeneration in the cerebral cortex and hippocampal areas of the brain while unvaccinated mice showed significant degeneration of the brain after Zika infection. Prior preclinical studies have tested potential Zika vaccine candidates in animal models involving normal mice and non-human primates that are naturally resistant to Zika. While providing useful immunology data, they cannot provide relevant evidence of an effective means of controlling the spread or medical impacts of this disease by vaccination. In addition to reporting immunogenicity in such Zika-resistant species, this paper represents the first published research to also analyze a Zika vaccine using the special transgenic murine strain A129 lacking interferon alpha and beta receptors (IFNAR-/-), making them highly susceptible to Zika infection and disease. Taking this extra step provided data on how vaccine-generated immune responses could protect against a lethal viral challenge and demonstrates the benefit a Zika vaccine might provide in people. Dr. J. Joseph Kim, President and CEO of Inovio, said, “We clearly demonstrated the power and speed of our product development platform when we and our collaborators moved our Zika vaccine from the bench to human clinical studies in less than six months, a vaccine industry record. We’re pleased to now build further evidence of the potential utility of our product.” “Our results support the critical importance of immune responses for both preventing infection as well as ameliorating disease caused by the Zika virus,” said lead researcher David B. Weiner, Ph.D., Executive Vice President and Director of the Vaccine Center at The Wistar Institute and the W.W. Smith Charitable Trust Professor in Cancer Research at Wistar. Dr. Weiner is also a member of Inovio’s board of directors and chairs its scientific advisory board. “As the threat of Zika continues, these results further encourage the study of this vaccine as a preventative approach for protecting humans.” This study demonstrated that Inovio’s synthetic DNA vaccine expressed antigens specific to Zika and generated robust antigen-specific and neutralizing antibody and T cell responses in mouse and non-human primate models. Moreover, the study also demonstrated that GLS-5700 provided protection against the disease and death in Zika-susceptible A129 transgenic mice while also being neuroprotective, meaning the disease was unable to spread to the brain. This is especially important given the risk that babies born with the disease have of developing microcephaly, a birth defect resulting in an abnormally small head and that may prevent the brain from developing properly. This Zika vaccine was developed in a collaboration between Inovio Pharmaceuticals, Inc., The Wistar Institute, and GeneOne Life Science Inc. and is currently in two human clinical studies. Inovio expects to report phase I data before the end of this year from the first 40-subject study being conducted in Miami, Philadelphia and Quebec City. In August, the companies initiated a second study of GLS-5700 in 160 subjects in Puerto Rico. The CDC estimates that Zika will infect more than 25 percent of the Puerto Rican population by the end of the year, providing the potential for this study’s placebo control design to provide exploratory signals of vaccine efficacy in 2017. Inovio is taking immunotherapy to the next level in the fight against cancer and infectious diseases. We are the only immunotherapy company that has reported generating T cells in vivo in high quantity that are fully functional and whose killing capacity correlates with relevant clinical outcomes with a favorable safety profile. With an expanding portfolio of immune therapies, the company is advancing a growing preclinical and clinical stage product pipeline. Partners and collaborators include MedImmune, The Wistar Institute, University of Pennsylvania, DARPA, GeneOne Life Science, Plumbline Life Sciences, Drexel University, NIH, HIV Vaccines Trial Network, National Cancer Institute, U.S. Military HIV Research Program, and Laval University. For more information, visit www.inovio.com. This press release contains certain forward-looking statements relating to our business, including our plans to develop electroporation-based drug and gene delivery technologies and DNA vaccines, our expectations regarding our research and development programs and our capital resources. Actual events or results may differ from the expectations set forth herein as a result of a number of factors, including uncertainties inherent in pre-clinical studies, clinical trials and product development programs, including the Zika vaccine GLS-5700, the availability of funding to support continuing research and studies in an effort to prove safety and efficacy of electroporation technology as a delivery mechanism or develop viable DNA vaccines, our ability to support our broad pipeline of SynCon® active immunotherapy and vaccine products, the ability of our collaborators to attain development and commercial milestones for products we license and product sales that will enable us to receive future payments and royalties, the adequacy of our capital resources, the availability or potential availability of alternative therapies or treatments for the conditions targeted by the company or its collaborators, including alternatives that may be more efficacious or cost effective than any therapy or treatment that the company and its collaborators hope to develop, issues involving product liability, issues involving patents and whether they or licenses to them will provide the company with meaningful protection from others using the covered technologies, whether such proprietary rights are enforceable or defensible or infringe or allegedly infringe on rights of others or can withstand claims of invalidity and whether the company can finance or devote other significant resources that may be necessary to prosecute, protect or defend them, the level of corporate expenditures, assessments of the company's technology by potential corporate or other partners or collaborators, capital market conditions, the impact of government healthcare proposals and other factors set forth in our Annual Report on Form 10-K for the year ended December 31, 2015, our Form 10-Q for the quarter ended September 30, 2016, and other regulatory filings from time to time. There can be no assurance that any product in Inovio's pipeline will be successfully developed or manufactured, that final results of clinical studies will be supportive of regulatory approvals required to market licensed products, or that any of the forward-looking information provided herein will be proven accurate.


News Article | November 10, 2016
Site: www.eurekalert.org

PHILADELPHIA--(Nov. 10, 2016)-- As the global spread of the Zika virus continues, efforts are underway to halt the disease's transmission. While no licensed therapies or vaccines to protect against the Zika virus are currently available, new research published in the journal npj Vaccines demonstrates how a synthetic DNA vaccine approach successfully protected against infection, brain damage and death caused by the mosquito-borne Zika virus in vivo. In this preclinical study, 100 percent of the animal models were protected from Zika after vaccination followed by a challenge with the Zika virus. In addition, they were protected from degeneration in the cerebral cortex and hippocampal areas of the brain, while the other cohort showed degeneration of the brain after Zika infection. "Our results support the critical importance of immune responses for both preventing infection as well as ameliorating disease caused by the Zika virus," said lead researcher David B. Weiner, Ph.D., Executive Vice President and Director of the Vaccine Center at The Wistar Institute and the W.W. Smith Charitable Trust Professor in Cancer Research at Wistar. "As the threat of Zika continues, these results provide insight into a new aspect of the possibly protective ability of such a vaccine as a preventative approach for Zika infection." This study is the first of its kind to analyze a vaccine in an animal model that is susceptible to the disease, providing information regarding the protective impact of the immune response in susceptible individuals. Prior studies of the Zika virus have tested vaccines in animal models that are naturally resistant to Zika. This study extends these prior research studies in an important manner. J. Joseph Kim, Ph.D., MBA, President and CEO of Inovio Pharmaceuticals, Inc., added, "Working with Wistar, we have clearly demonstrated the power and the speed of our product development platform when we and our collaborators moved our Zika vaccine from the bench to human studies in less than six months, taking advantage of our platform to help in this outbreak situation. In this latest study, Weiner and colleagues demonstrated how a synthetic DNA vaccine expressed specific antigens for Zika in vivo. They observed that this novel vaccine generated robust antigen-specific antibody and T cell responses that neutralized the virus in preclinical animal models. Moreover, they found that the vaccine provided protection against the disease and death in animal models while also being neuroprotective, meaning that the disease was unable to spread to the brain. This is especially important given the risk that infants born with the disease have of developing microcephaly, a birth defect resulting in an abnormally small head and that may prevent the brain from developing properly. One important aspect of Zika and many other mosquito-borne diseases is that not everyone infected with the virus will actually become ill as a result. With Zika, only about 20 to 25 percent of individuals with the virus are actually impacted by the disease, according to previous studies from the U.S. Centers for Disease Control (CDC). However, there is no way to know for certain who will be at risk for illness due to the virus, which is why it was crucial for this study to examine how a vaccine would operate in an infected, symptomatic host. This Zika vaccine is being developed in collaboration between Inovio, The Wistar Institute, and GeneOne Life Science Inc. and is currently being tested in two human clinical studies. Before the end of 2016, Inovio expects to report phase I data from the first 40-subject study being conducted in Miami, Philadelphia and Quebec City. In August, the companies also initiated a second study in 160 subjects in Puerto Rico. The CDC estimates that Zika will infect more than 25 percent of the Puerto Rican population by the end of the year, creating the potential for this study's placebo-controlled design to provide exploratory signals of vaccine efficacy in 2017. A total of nearly 4,000 cases of Zika infection have been reported in the United States alone, according to the CDC. While most of these are travel-associated cases, more than 100 cases of Zika infection originating within the United States have been reported. Globally, more than 60 countries have reported mosquito-borne transmission of the disease. This work was supported by the National Institutes of Health and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases grant NIH R01 AI092843. Weiner received funding from Inovio Pharmaceuticals Inc. and Gene One Life Science Inc. Co-authors of this study from The Wistar Institute include Karuppiah Muthumani, Sangya Agarwal, Sagar Kudchodkar, Emma Reuschel, Hyeree Choi, Elizabeth Duperret, Chistopher Chung, and Yinho Kim. Other co-authors of this study include Bryan Griffin, Stephanie Booth, Trina Racine, and Gary Kobinger from the Public Health Agency of Canada; Kim Kraynyak, Jian Yan, Matthew Morrow, Jingjing Jiang, Brian Lee, Stephanie Ramos, Kate Broderick, Charles Reed, Niranjan Y. Sardesai, and J. Joseph Kim from Inovio Pharmaceuticals, Inc.; Amelia Anne Keaton from the Children's Hospital of Philadelphia; Kenneth Ugen from the University of South Florida Morsani College of Medicine; and Young Park and Joel Maslow from GeneOne Life Science Inc. The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.


News Article | November 10, 2016
Site: www.sciencedaily.com

As the global spread of the Zika virus continues, efforts are underway to halt the disease's transmission. While no licensed therapies or vaccines to protect against the Zika virus are currently available, new research published in the journal npj Vaccines demonstrates how a synthetic DNA vaccine approach successfully protected against infection, brain damage and death caused by the mosquito-borne Zika virus in vivo. In this preclinical study, 100 percent of the animal models were protected from Zika after vaccination followed by a challenge with the Zika virus. In addition, they were protected from degeneration in the cerebral cortex and hippocampal areas of the brain, while the other cohort showed degeneration of the brain after Zika infection. "Our results support the critical importance of immune responses for both preventing infection as well as ameliorating disease caused by the Zika virus," said lead researcher David B. Weiner, Ph.D., Executive Vice President and Director of the Vaccine Center at The Wistar Institute and the W.W. Smith Charitable Trust Professor in Cancer Research at Wistar. "As the threat of Zika continues, these results provide insight into a new aspect of the possibly protective ability of such a vaccine as a preventative approach for Zika infection." This study is the first of its kind to analyze a vaccine in an animal model that is susceptible to the disease, providing information regarding the protective impact of the immune response in susceptible individuals. Prior studies of the Zika virus have tested vaccines in animal models that are naturally resistant to Zika. This study extends these prior research studies in an important manner. J. Joseph Kim, Ph.D., MBA, President and CEO of Inovio Pharmaceuticals, Inc., added, "Working with Wistar, we have clearly demonstrated the power and the speed of our product development platform when we and our collaborators moved our Zika vaccine from the bench to human studies in less than six months, taking advantage of our platform to help in this outbreak situation. In this latest study, Weiner and colleagues demonstrated how a synthetic DNA vaccine expressed specific antigens for Zika in vivo. They observed that this novel vaccine generated robust antigen-specific antibody and T cell responses that neutralized the virus in preclinical animal models. Moreover, they found that the vaccine provided protection against the disease and death in animal models while also being neuroprotective, meaning that the disease was unable to spread to the brain. This is especially important given the risk that infants born with the disease have of developing microcephaly, a birth defect resulting in an abnormally small head and that may prevent the brain from developing properly. One important aspect of Zika and many other mosquito-borne diseases is that not everyone infected with the virus will actually become ill as a result. With Zika, only about 20 to 25 percent of individuals with the virus are actually impacted by the disease, according to previous studies from the U.S. Centers for Disease Control (CDC). However, there is no way to know for certain who will be at risk for illness due to the virus, which is why it was crucial for this study to examine how a vaccine would operate in an infected, symptomatic host. This Zika vaccine is being developed in collaboration between Inovio, The Wistar Institute, and GeneOne Life Science Inc. and is currently being tested in two human clinical studies. Before the end of 2016, Inovio expects to report phase I data from the first 40-subject study being conducted in Miami, Philadelphia and Quebec City. In August, the companies also initiated a second study in 160 subjects in Puerto Rico. The CDC estimates that Zika will infect more than 25 percent of the Puerto Rican population by the end of the year, creating the potential for this study's placebo-controlled design to provide exploratory signals of vaccine efficacy in 2017. A total of nearly 4,000 cases of Zika infection have been reported in the United States alone, according to the CDC. While most of these are travel-associated cases, more than 100 cases of Zika infection originating within the United States have been reported. Globally, more than 60 countries have reported mosquito-borne transmission of the disease.


News Article | February 24, 2017
Site: www.eurekalert.org

PHILADELPHIA -- (Feb. 24, 2017) -- Scientists at The Wistar Institute and Inovio Pharmaceuticals, Inc. have devised a novel DNA vaccine approach through molecular design to improve the immune responses elicited against one of the most important cancer antigen targets. Study results were published in the journal Molecular Therapy. Cancer immunotherapy approaches, designed to harness the body's natural immune defenses to target and kill cancer cells, are showing great promise for cancer treatment and prevention. DNA vaccines can induce immunity through the delivery by an intramuscular injection of a sequence of synthetically designed DNA that contains the instructions for the immune cells in the body to become activated and target a specific antigen against which an immune response is sought. This approach has proven effective in generating strong immunity against some infectious diseases as well as clearing neoplasia in patients with tumors caused by viral infection. The recent identification of tumor-associated antigens, or proteins that are specifically expressed by tumor cells and not by normal cells, has sparked the development of DNA vaccine approaches against some of these promising targets. Unfortunately, most vaccines targeting tumor-associated antigens have had limited success so far in producing therapeutic effects against most cancers due to poor immunogenicity. Despite being specific for tumor cells, tumor-associated antigens typically trigger weak immune responses because they are recognized as self-antigens and the body has in place natural mechanisms of immune acceptance, or "tolerance", that prevent autoimmunity but also limit the efficacy of cancer vaccines. This is the case of Wilm's tumor gene 1 (WT1), a tumor antigen that is overexpressed in many types of cancer and likely plays a key role in driving tumor development. Vaccine approaches against WT1 so far have not appeared promising due to immune tolerance resulting in poor immune responses against cancers expressing WT1. Wistar scientists have developed a novel WT1 DNA vaccine using a strategically modified DNA sequence that tags the WT1 as foreign to the host immune system breaking tolerance in animal models. "This is an important time in the development of anti-cancer immune therapy approaches. This team has developed an approach that may play an important role in generating improved immunity to WT1 expressing cancers," said David B. Weiner, Ph.D., Executive Vice President and Director of the Vaccine Center at The Wistar Institute and the W.W. Smith Charitable Trust Professor in Cancer Research, and senior author of the study. "These immune responses represent a unique tool for potentially treating patients with multiple forms of cancer. Our vaccine also provides an opportunity to combine this approach with another immune therapy approach, checkpoint inhibitors, to maximize possible immune therapy impact on specific cancers." The team lead by Weiner has optimized the DNA vaccine using a synthetic DNA sequence for WT1 that, while maintaining a very high homology with the native sequence, contains new changed sequences that differ from native WT1 in an effort to render it more recognizable by the host immune system. This study shows that this novel vaccine design was able to induce WT1-specific, robust T cell responses as well as antibody production with no apparent toxicity both in mice and in non-human primates. The novel WT1 vaccine was superior to a more traditional native WT1 vaccine because it was able to break immune tolerance and induce long term immune memory. Importantly, the vaccine also stimulated a therapeutic anti-tumor response against leukemia in mice. This work was supported by grants from Inovio Pharmaceuticals, Inc. and the Basser Center for BRCA at the Abramson Cancer Center. Weiner is supported by the W.W. Smith Charitable Trust Professorship for Cancer Research. Co-authors of this study from The Wistar Institute include: Elizabeth K. Duperret and Jaemi Chu. Other co-authors include: Jewell N. Walters, Bernadette Ferraro, Kimberly A. Kraynyak, Jian Yan, Amir S. Khan and Niranjan Y. Sardesai from Inovio Pharmaceuticals, Inc., Ashley Saint-Fleur, and Hyam I. Levitsky from The Johns Hopkins University School of Medicine, Baltimore, Md. The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.


Chang J.-Y.,National Health Research Institute | Chang J.-Y.,Vaccine Center | Chang C.-P.,National Health Research Institute | Chang C.-P.,Vaccine Center | And 17 more authors.
Vaccine | Year: 2012

Enterovirus 71 (EV71) has recently emerged as an important neurotropic virus in Asia because effective medications and prophylactic vaccine against EV71 infection are not available. Based on the success of inactivated poliovirus vaccine, the Vero cell-based chemically inactivated EV71 vaccine candidate could be developed. Identification of EV71 vaccine strain which can grow to high titer in Vero cell and induce cross-genotype virus neutralizing antibody responses represents the first step in vaccine development. In this report we describe the characterization and validation of a clinical isolate E59 belonging to B4 sub-genotype based on VP1 genetic analysis. Before selected as the vaccine strain, the genetic stability of E59 in passage had been analyzed based on the nucleotide sequences obtained from the Master Virus Seed, Working Seed banks and the virus harvested from the production lots, and found to be identical to those found in the original isolate. These results indicate that E59 vaccine strain has strong genetic stability in passage. Using this vaccine strain the prototype EV71 vaccine candidate was produced from 20. L of Vero cell grown in serum-containing medium. The production processes were investigated, characterized and quantified to establish the potential vaccine manufacturing process including the time for virus harvest, the membrane for diafiltration and concentration, the gel-filtration chromatography for the down-stream virus purification, and the methods for viral inactivation. Finally, the inactivated virion vaccine candidate containing sub-microgram of viral proteins formulated with alum adjuvant was found to induce strong virus neutralizing antibody responses in mice and rabbits. Therefore, these results provide valuable information for cell-based EV71 vaccine development. © 2011 Elsevier Ltd.


Chou A.-H.,National Health Research Institute | Liu C.-C.,National Health Research Institute | Chang C.-P.,National Health Research Institute | Guo M.-S.,National Health Research Institute | And 15 more authors.
PLoS ONE | Year: 2012

Background: Enterovirus 71 (EV71) has caused several epidemics of hand, foot and mouth diseases (HFMD) in Asia and now is being recognized as an important neurotropic virus. Effective medications and prophylactic vaccine against EV71 infection are urgently needed. Based on the success of inactivated poliovirus vaccine, a prototype chemically inactivated EV71 vaccine candidate has been developed and currently in human phase 1 clinical trial. Principal Finding: In this report, we present the development of a serum-free cell-based EV71 vaccine. The optimization at each step of the manufacturing process was investigated, characterized and quantified. In the up-stream process development, different commercially available cell culture media either containing serum or serum-free was screened for cell growth and virus yield using the roller-bottle technology. VP-SFM serum-free medium was selected based on the Vero cell growth profile and EV71 virus production. After the up-stream processes (virus harvest, diafiltration and concentration), a combination of gel-filtration liquid chromatography and/or sucrose-gradient ultracentrifugation down-stream purification processes were investigated at a pilot scale of 40 liters each. Although the combination of chromatography and sucrose-gradient ultracentrifugation produced extremely pure EV71 infectious virus particles, the overall yield of vaccine was 7-10% as determined by a VP2-based quantitative ELISA. Using chromatography as the downstream purification, the virus yield was 30-43%. To retain the integrity of virus neutralization epitopes and the stability of the vaccine product, the best virus inactivation was found to be 0.025% formalin-treatment at 37°C for 3 to 6 days. Furthermore, the formalin-inactivated virion vaccine candidate was found to be stable for >18 months at 4°C and a microgram of viral proteins formulated with alum adjuvant could induce strong virus-neutralizing antibody responses in mice, rats, rabbits, and non-human primates. Conclusion: These results provide valuable information supporting the current cell-based serum-free EV71 vaccine candidate going into human Phase I clinical trials. © 2012 Chou et al.


News Article | February 26, 2017
Site: www.techtimes.com

One of the major causes of morbidity and mortality in the world, cancer seems unstoppable. A novel DNA vaccine developed by scientists at the Wistar Institute and Inovio Pharmaceuticals, Inc., however, shows promising potential for the treatment of cancer. Cancer vaccines are biological response modifiers, which work by stimulating or repairing the immune system's capacity to ward off infections and disease. There are two main types of cancer vaccines: Preventive or prophylactic vaccines, which proactively protects a healthy person from getting cancer. Human papillomavirus (HPV) vaccines and hepatitis B vaccines are two examples of preventive vaccines. Treatment or therapeutic vaccine, on the other hand, is a form of immunotherapy that fights off existing cancers. In April 2010, the U.S. Food And Drug Administration (FDA) approved the first cancer treatment vaccine, sipuleucel-T (Provenge®), for men with metastatic prostate cancer. Using modified DNA sequence, the new WT1 DNA vaccine is explicitly designed to improve immune responses against Wilm's tumor gene 1 (WT1), a tumor-associated antigen seen in several types of cancer, which experts believe plays a pivotal part in tumor development. A cut above the rest of WT1 vaccine approaches, the latest WT1 DNA vaccine identifies the WT1 antigen as foreign to the immune system, disrupting existing immune acceptance or tolerance for it. Immune tolerance hinders autoimmunity and impedes vaccine efficacy. "This team has developed an approach that may play an important role in generating improved immunity to WT1 expressing cancers. These immune responses represent a unique tool for potentially treating patients with multiple forms of cancer," David B. Weiner, Ph.D., a principal author of the study and Wistar Institute's Executive Vice President and Director of the Vaccine Center, stated. Weiner also mentioned that the latest WT1 vaccine can be used in adjunct with other immune therapies, checkpoint inhibitors for best results. The study was published in the journal Molecular Therapy. The highest incidences of cancer mortality were seen in lung cancer (1.69 million deaths), liver cancer (788,000 deaths), colorectal cancer (774,000 deaths), stomach cancer (754,000 deaths), and breast cancer (571,000 deaths). Approximately 14 million new diagnoses were made in 2012. Unfortunately, the figures are continuously soaring, with new cancer cases expected to shoot up to 70 percent in the next 20 years. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.

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