Author: The Wistar Institute

In Memory of Harold Davis, an Extraordinary Wistar Supporter

Written by The Wistar Institute on April 2, 2019. Posted in Featured News.

The Wistar community mourns the loss of a dear friend and one of our greatest supporters, who has given of himself generously to help Wistar for more than four decades.

Harold (Hal) M. Davis passed away on Wednesday, Feb. 27, 2019.

A successful Philadelphia businessman with a big heart and co-founder of Realen Homes in 1967, Hal joined the Wistar Board of Trustees in 1987, when then Board chair Bob Fox was searching for just the right board member to help guide the Institute. Hal accepted the invitation with enthusiasm. He was a conscientious board member, available at any time, willing to help in any area. During his 20 years on the Board, he provided counsel as Development Chair and then as Vice Chair. He was also involved in the efforts for the construction of Wistar’s Robert and Penny Fox Research Tower, which opened in 2014.

Hal and his wife Eleanor were passionate about supporting cancer research.

“My family history is one of cancer and I’ve always felt cancer is the worst possible disease you could have,” Hal used to say. The Davis family supported breast cancer research at Wistar through the Christopher M. Davis Memorial Fund, established in 1996 in memory of their son Christopher. Subsequently, the Christopher M. Davis Memorial Fellowship was created to support a postdoctoral fellow conducting breast cancer research at Wistar. This endowed fellowship had a profound impact on the 14 fellows it funded and on the work that was accomplished in the nine laboratories that were supported.

In 2013, thanks to the generosity of the Davis family, the fellowship was transformed into the endowed Christopher M. Davis Professorship, which was appointed to Dmitry I. Gabrilovich, M.D., Ph.D., professor and program leader in the Immunology, Microenvironment and Metastasis Program of Wistar’s National Cancer Institute-designated Cancer Center.

“Hal and Eleanor have been Wistar’s steadfast partners for 40 years and were pivotal in fostering a transformed and reimagined Wistar Institute,” said Russel E. Kaufman, M.D., Wistar’s President Emeritus, who enjoyed Hal’s friendship and advice during his time at the helm of the Institute. “Hal was a generous, loyal and committed man who, when he believed in a cause like Wistar, got behind it 100%. He was truly extraordinary and will be greatly missed.”

Wistar and the Philadelphia Zoo Work Together to Improve Global Health

Written by The Wistar Institute on March 21, 2019. Posted in Featured News.

The Wistar Institute and the Philadelphia Zoo employ different preventative approaches to improve the health of humans and animals around the world. The Zoo uses conservation and education while Wistar uses biomedical research in vaccines and infectious disease to achieve the One Health goal set by the Center for Disease Control.

The Wistar Institute and the Philadelphia Zoo, two esteemed organizations with a long history in Philadelphia — the first independent research institute and the first zoo in the country, showcased a partnership to advance the global message of “One Health” throughout the region in an event held at the Zoo.

One Health is a collaborative, multisectoral and transdisciplinary approach operating at the local, regional, national, and global levels with the goal of improving the lives of people and animals through the collaboration of human medicine, research and conservation science, among other fields of study.

Immersed in the atmosphere of the Zoo’s Small Mammal House, the guests heard about the intrinsic link between the health of people and animals and how Wistar and the Philadelphia Zoo enact the One Health approach.

Michael Stern, Philadelphia Zoo curator of primates and small mammals, presented a successful international conservation initiative of the Zoo to preserve the Rodrigues Fruit Bat, a story that perfectly encapsulates the Zoo’s vision of a future in which people and animals thrive together recognizing that what is good for wildlife can also be good for people.

Rodrigues is a small island located 900 miles east of Madagascar. At the time of its discovery, it was a hotbed of biodiversity with many endemic plant and vertebrate species. Less than 200 years after human colonization, the majority of these species were lost or threatened, and this paradise turned into barren land. By the 1970s, less than 100 Rodrigues Fruit Bats had remained on the island and they had officially become the rarest bat species in the world.

The staff from the Philadelphia Zoo began conservation efforts in Rodrigues in 1995. Leveraging the Zoo’s consistent engagement and financial support, the Mauritian Wildlife Foundation that has taken over the project has obtained funding to grow the conservation program, which now includes reforestation efforts, community engagement, planting native seedlings to create more roosts and food for the bats and other species. The local government fully supports the work and has even started subsidizing cooking gas to reduce the need for deforestation for cooking fuel.

As a result, forests and the bat population rebounded and by 2013 had reached almost 20,000 individuals. In 2017, the Rodrigues Fruit Bat was down listed from “critically endangered” to “endangered” and other species on the island have been down listed too.

David B. Weiner, Ph.D., the W.W. Smith Charitable Trust Professor in Cancer Research, Wistar executive vice president and director of the Vaccine & Immunotherapy Center, provided a perspective on zoonotic diseases, which are caused by infections that spread between animals and people, and the interconnectedness of animals, people and their shared environment. He spoke to past and current biomedical research contributions that Wistar has made to the health of people and animals, including vaccines against rabies for people and wildlife that have helped to make rabies-related human death a rarity in the U.S. and many other countries.

Often the animals are primary hosts for zoonotic viruses and do not get sick from them, but they can pass it on to other species and to people. We humans can also infect animals with our diseases. Examples of zoonotic diseases are Zika, Ebola, SARS, Nipah, MERS, influenza, and rabies, all of which are research areas at Wistar.

Zoonotic diseases are a major global health concern today: the human population is continuously expanding to new areas and humans are coming in close contact with wild animals that can carry diseases; climate change is modifying environmental conditions and habitats creating more opportunities for diseases to pass to animals; international travel and trade facilitate the fast spread of disease across the globe. Finally, we, as a population, have changed too: now there are many immunocompromised individuals living throughout the world, such as cancer survivors and organ transplant recipients, and we live longer so our immune system gets weaker as we age.

Wistar is now tackling many infectious diseases with next generation synthetic DNA vaccines, which are different from traditional vaccines in that they don’t contain viruses and are faster to develop, having the potential to provide adequate response to fast-emerging outbreaks. Wistar scientists have taken this approach to the clinic and shown that DNA vaccines are safe and able to produce robust immune responses. They are currently developing DNA vaccines for Ebola, MERS and Zika that have gone from preclinical to human studies in just months.

Wistar and the Philadelphia Zoo look forward to working together in the future to continue to keep animals and people healthy.

A Global Approach to Health and Conservation

New Small Molecule Inhibitors Show Potential for Treatment of Epstein-Barr Virus-Associated Cancers

Written by The Wistar Institute on March 6, 2019. Posted in Press Releases.

PHILADELPHIA — (March 6, 2019) — Researchers at The Wistar Institute have created a drug candidate for cancers associated with Epstein-Barr Virus (EBV), the virus that causes infectious mononucleosis. In a study published in Science Translational Medicine, they described inhibitors of an EBV protein called Epstein-Barr Nuclear Antigen 1 (EBNA1), showing efficacy in preclinical models.

More than 90% of adults are infected with EBV worldwide. The virus establishes life-long, latent infection in B lymphocytes, which is, in rare cases, associated with development of different cancer types, including Burkitt’s lymphoma, nasopharyngeal carcinoma (NPC) and Hodgkin’s lymphoma. EBNA1 is a DNA-binding protein critical for virus replication and for continuous proliferation of infected cells.

“EBNA1 is found in all EBV-associated tumors and does not look like any other protein in the human body,” said Paul M. Lieberman, Ph.D., Hilary Koprowski, M.D., Endowed Professor, leader of the Gene Expression & Regulation Program at Wistar, and corresponding author on the study. “These characteristics, along with the protein’s particular structure, make EBNA1 a very attractive therapeutic target.”

Based on the 3-D structure of the protein, Lieberman and colleagues created a class of small molecule inhibitors of EBNA1 that block its ability to bind to DNA, as confirmed in EBV-infected NPC cells.

The efficacy of these inhibitors was tested in vivo in relevant mouse models of EBV-associated cancers, established by transplanting tumor cells or patient-derived tumor samples into immunocompromised mice. Researchers observed a dramatic reduction in tumor growth in all conditions tested. The tumor growth inhibition was greater than that achieved with gamma irradiation or chemotherapy, which are the standard-of-care treatments for NPC patients.

“It has taken the lab nearly a decade to go from concept to identifying a clinical candidate,” said Troy E. Messick, Ph.D., first and co-corresponding author on the study and senior staff scientist in the Lieberman Lab. “We are excited about the activity of these inhibitors in a number of preclinical studies and look forward to the next steps of development.”

Pharmacological inhibition of EBNA1 had profound effects on gene expression of both EBV and host-cell genes, which correlated with substantial decrease in EBV DNA copy number and suppression of EBV-driven tumor promoting pathways.

Importantly, tests showed a favorable pharmacological profile and little to no evidence of drug resistance after prolonged treatment.

The Wistar Institute has granted an exclusive worldwide license for the development and commercialization of VK-2019, an EBNA1 inhibitor, to Cullinan Apollo Corp., a wholly owned subsidiary of Cullinan Oncology, LLC. Cullinan anticipates initiating enrollment in a global phase 1/2 clinical study in the second quarter of 2019.

Co-authors: Samantha S. Soldan, Julianna S. Deakyne, Kimberly A. Malecka, Lois Tolvinski, Donna H. Tran, and Benjamin R. Wassermann from Wistar. Garry R. Smith, Mark E. McDonnell, Yan Zhang, Venkata Velvadapu, and Allen B. Reitz from Fox Chase Chemical Diversity Center, Inc; A. Pieter J. van den Heuvel, Bai-Wei Gu and Joel A. Cassel from Vironika, LLC; Pierre Busson from Institut Gustave Roussy, France; and Edward R. Zartler from Quantum Tessera Consulting, LLC.

Work supported by: National Institutes of Health (NIH) grants R43AI079928, R43AI096588, R44AI096588, R01CA093606, R01DE017336, and T32 CA09171; and two Seeding Drug Discovery grants from Wellcome (WT096496/Z/11/Z). Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30CA010815.

Publication information: Structure-based design of small molecule inhibitors of EBNA1 DNA-binding blocks Epstein-Barr virus latent infection and tumor growth, Science Translational Medicine (2019). Advance online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious disease 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.

The Wistar Institute and Anixa Biosciences Extend Collaborative Research Agreement

Written by The Wistar Institute on February 21, 2019. Posted in Press Releases.

Philadelphia and San Jose, Calif. – (Feb. 21, 2019) – The Wistar Institute has extended its collaboration with Anixa Biosciences, Inc. (NASDAQ: ANIX), a biotechnology company focused on using the body’s immune system to fight cancer. The project is focused on understanding the role of myeloid-derived suppressor cells (MDSCs) and how they can be used in diagnostic and therapeutic applications—work advanced by Dmitry I. Gabrilovich, M.D., Ph.D., considered a pioneer in the field of MDSC biology and the roles this cell population plays in cancer progression and therapy response.

“We are pleased to continue our collaboration with our long-time partner, The Wistar Institute,” stated Amit Kumar, Ph.D., President and CEO of Anixa Biosciences. “With support from Wistar and in collaboration with their laboratories and personnel, we have made tremendous progress with our Cchek™ cancer detection technology and in gaining a greater understanding of the role of MDSCs in cancer.”

“Our joint project has focused on discovering and validating new markers that can identify MDSCs,” stated Dmitry I. Gabrilovich, M.D., Ph.D., Professor and Leader of the Immunology, Microenvironment and Metastasis Program at The Wistar Institute. “We are pleased to be continuing this collaboration with Anixa. Our goal is to continue to understand the behavior of MDSCs, which are now known to play a major role in enabling tumors to evade and escape the immune system.”

Heather A. Steinman, Ph.D., M.B.A., Vice President for Business Development and Executive Director for Technology Transfer at The Wistar Institute stated, “Anixa has been a wonderful partner of ours for years, and we are looking forward to continuing our fruitful collaboration.”

About The Wistar Institute
The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious disease 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’s Business Development team is dedicated to advancing Wistar science and technology development through creative partnerships. wistar.org.

About Anixa Biosciences, Inc.
Anixa, a cancer-focused biotechnology company, is harnessing the body’s immune system in the fight against cancer. Anixa is developing both diagnostics and therapeutics to detect cancer early, when it is most curable, and to treat those afflicted once diagnosed. It is developing the CchekTM platform, a series of inexpensive non-invasive blood tests for the early detection of solid tumors, which is based on the body’s immune response to the presence of a malignancy. It is also developing chimeric antigen receptor T-cell (CAR-T) based immuno-therapy drugs which genetically engineer a patient’s own immune cells to fight cancer. Anixa also continually examines emerging technologies in complementary or related fields for further development and commercialization. Additional information is available at www.anixa.com.

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Forward-Looking Statements: Statements that are not historical fact may be considered forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are not statements of historical facts, but rather reflect Anixa’s current expectations concerning future events and results. We generally use the words “believes,” “expects,” “intends,” “plans,” “anticipates,” “likely,” “will” and similar expressions to identify forward-looking statements. Such forward-looking statements, including those concerning our expectations, involve risks, uncertainties and other factors, some of which are beyond our control, which may cause our actual results, performance or achievements, or industry results, to be materially different from any future results, performance, or achievements expressed or implied by such forward-looking statements. These risks, uncertainties and factors include, but are not limited to, those factors set forth in “Item 1A – Risk Factors” and other sections of our most recent Annual Report on Form 10-K as well as in our Quarterly Reports on Form 10-Q and Current Reports on Form 8-K. We undertake no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. You are cautioned not to unduly rely on such forward-looking statements when evaluating the information presented in this press release.

Media Contacts:

Anixa Biosciences, Inc.:
Mike Catelani
(408) 708-9808
mcatelani@anixa.com

The Wistar Institute:
Darien Sutton
(215) 898-3988
dsutton@wistar.org

New Insight Into the Balance Between the Tumor-suppressive and Tumor-promoting Effects of Cellular Senescence

Written by The Wistar Institute on February 18, 2019. Posted in Press Releases.

PHILADELPHIA — (Feb. 18, 2019) — Researchers at The Wistar Institute have described a novel role of nicotinamide adenine dinucleotide (NAD+) metabolism in the ability of senescent cells to release tumor-promoting molecules. This study, published online in Nature Cell Biology, also cautions that NAD+-augmenting supplements, currently in development for their anti-aging effects as nutroceuticals, should be administered with precision given their potential pro-tumorigenic side effects.

Cellular senescence is a process in which cells irreversibly stop dividing and represents a potent tumor suppressive mechanism. At the same time, senescent cells also produce a variety of inflammatory soluble molecules that can promote tumor growth, known by the name of senescence-associated secretory phenotype (SASP).

The laboratory of Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center, professor and co-program leader of the Gene Expression and Regulation Program, investigated the role of a family of proteins called HMGAs in cellular senescence and the SASP.

HMGAs are DNA-binding proteins that regulate gene expression. They are frequently overexpressed and associated with poor prognosis in many cancer types, yet they are known to promote senescence. This new research aims to clarify these mechanisms to unveil the dual role of the HMGA family of proteins in cancer.

Zhang and colleagues discovered that in cells undergoing senescence HMGAs increase the levels of NAMPT, a key enzyme in the production of nicotinamide adenine dinucleotide (NAD+), a cellular factor critical for metabolism and enzyme function. Importantly, increased NAD+ levels enhanced the SASP.

“Our data show that NAD+ levels influence the secretory activity of senescent cells in a way that may promote tumor progression,” said Zhang. “It is well documented that cellular NAD+ concentrations decrease during aging and the use of NAD+ supplementation is being studied as a new preventive opportunity for aging and age-associated disorders. Our results may have far-reaching implications on this field of investigation.”

In fact, by manipulating the expression of HMGA1 and NAMPT, the researchers observed that increased NAD+ metabolism promotes cancer cell proliferation and progression in vivo in mouse models of pancreatic and ovarian cancers.

These data point to a model whereby increased NAD+ metabolism resulting from higher HMGA1 and NAMPT expression promotes a higher SASP and enhances the inflammatory environment around the tumor, which in turn has a stimulatory effect on cancer growth.

“We found that HMGA1 provides a link between the two opposite sides of the coin in the process of senescence — growth arrest and the tumor promoting, proinflammatory secretory phenotype,” said Zhang.

“Our data raise the possibility that targeting NAMPT may be an effective approach to suppress a proinflammatory, tumor promoting microenvironment in tumors that overexpress HMGA1 when treated with senescence-triggering cancer therapeutics such as chemotherapy and radiotherapy,” said Timothy Nacarelli, Ph.D., first author of the study and a postdoctoral researcher in the Zhang Lab. “NAMPT inhibitors are currently in clinical trials and thus readily available for these new applications.”

Co-authors: Takeshi Fukumoto, Joseph Zundell, Nail Fatkhutdinov, Shuai Wu, Katherine M. Aird, Osamu Iwasaki, Andrew V. Kossenkov, Ken-ichi Noma, Zachary Schug, Hsin-Yao Tang, and David W. Speicher from Wistar. Lena Lau and Gregory David from New York University School of Medicine; David Schultz and Joseph A. Baur from University of Pennsylvania.

Work supported by: National Institutes of Health (NIH) grants R01CA160331, R01CA163377, R01CA202919, P01AG031862, P50CA228991, R01CA148639, R21CA155736, F31CA206387, R00CA194309, R01DK098656, R01CA131582, R50CA211199, R50CA221838, and T32CA009191; U.S. Department of Defense grants OC140632P1 and OC150446. Additional support was provided by The Honorable Tina Brozman Foundation for Ovarian Cancer Research and Ovarian Cancer Research Alliance (Collaborative Research Development Grant and Ann and Sol Schreiber Mentored Investigator Award). Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30CA010815.

Publication information: NAD+ metabolism governs the proinflammatory senescence-associated secretome, Nature Cell Biology (2019). Advance online publication.

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You Are What You Eat: Linking Nutrition, Metabolism and Cancer

Written by The Wistar Institute on February 18, 2019. Posted in Featured News.

As the obesity epidemic climbs, and the connection between nutrition and its effects on health risks and outcomes are top of mind, Wistar’s most recent Women & Science Program featured a comprehensive talk on how what we eat is used by our cells for energy, and the connection to cancer development. The first program of this year was held fittingly during the week of International Day of Women and Girls in Science.

Guest speaker Kathryn Wellen, Ph.D., associate professor in the Department of Cancer Biology and the Abramson Family Cancer Research Institute at the University of Pennsylvania, took the audience on a journey through biochemistry, genetics and cell biology to explain how nutrition steers the cells’ metabolic choices and cancer behavior.

Wellen’s research centers on the mechanisms through which cells monitor the availability of nutrients, which are as critical as the fuel gauge in our cars. The answer lies in the epigenetic control of gene expression, or the mechanisms that cause genes to be switched on and off. Every cell in our body contains the same DNA sequence, but the way this is read changes from cell type to cell type and in response to environmental stimuli. This regulation happens through chemical modifications of DNA and its associated proteins.

A stunning example that Wellen gave of the environmental effect on gene expression and, as a consequence, on human health is the case of the famine that plagued part of the Dutch population towards the end of World War II. Babies conceived during that time were born heavier than normal and grew up to experience higher rates of obesity, diabetes and schizophrenia. The starvation in the Dutch Hunger Winter, as it is known, altered expression of certain genes in unborn children, and these alterations remained in place for the rest of the children’s lives, affecting their health.

As Wellen explained, at the cellular level what we eat is broken down into metabolites that are needed to carry out the chemical modifications of DNA required for epigenetic regulation of gene expression. Wellen studies these mechanisms and the influence of different nutrients on the activity of genes that are critical in cancer.

In the early 1900s, the first observation on the relation between metabolism and cancer came from Nobel laureate Otto Warburg, who discovered that cancer cells utilize different metabolic pathways than normal cells. With the discovery of the role of gene mutations in causing cancer, scientists realized that mutations can alter genes that control metabolism. The latest piece to the puzzle is being added by the work of Wellen and others that connects metabolic changes to epigenetic changes.

Many recent studies point to obesity as a strong risk factor for several types of cancers. Wellen cautioned about the critical role of nutrition in cancer prevention. Research has linked sugar consumption to obesity, an epidemic on the rise in the country. In the 1700s, the average amount of sugar consumed per person was four pounds a year; however, by the 1990s this number had spiked to a shocking 120 pounds a year.

Research also shows that diet can impact therapeutic responses in cancer patients, for example by regulating insulin levels. In broader terms, because of the link between metabolism and gene regulation, it is likely that adjusting patients’ diets could make a difference in how therapy works for them.

Wellen believes that a deeper understanding of these intricate conversations between diet, metabolism, epigenetics, and cancer is needed because it may point to vulnerabilities that could be exploited from a therapeutic perspective.

Wistar’s David B. Weiner, Ph.D., Awarded Prestigious Scientific Achievement Award from Life Sciences Pennsylvania

Written by The Wistar Institute on February 15, 2019. Posted in Press Releases.

PHILADELPHIA — (Feb. 15, 2019) — David B. Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center, and the W.W. Smith Charitable Trust Professor in Cancer Research at The Wistar Institute, has been named the recipient of this year’s Scientific Achievement Award from Life Sciences Pennsylvania. The organization, with its more than 800-member companies, has a single mission to make Pennsylvania a hub of innovation by creating a business and public policy environment that fosters life sciences growth and success.

“Our Scientific Achievement Award recognizes a scientist in the Pennsylvania life sciences community who has demonstrated outstanding achievement by advancing scientific knowledge, innovation, and/or patient care,” said Christopher P. Molineaux, president & CEO of Life Sciences PA. “We can’t think of a better honoree this year than David – considered a founder of the field of synthetic DNA vaccines with more than 30 years of research contributions and scientific influence.”

At Wistar, Weiner directs a translational research laboratory in the area of novel synthetic nucleic acid technologies. His lab’s accomplishments include the first in human studies of DNA vaccines and DNA-encoded monoclonal antibodies for treating and preventing cancer and emerging infectious diseases, clinically important advances in gene expression, optimization and DNA delivery. His lab developed the first clinically efficacious DNA vaccine and has moved synthetic DNA vaccines for Middle Eastern Respiratory Syndrome (MERS), HIV, Ebola, and Zika through development into clinical studies. Weiner is igniting collaboration to also explore combination therapies for ovarian, prostate, and other cancers.

The Weiner Lab has published more than 400 papers, chapters and reviews. Weiner has received multiple awards and honors, including the National Institutes of Health Director’s Transformative Research Award, the Vaccine Industry Excellence Award for Best Academic Research Team, and his lab was named among the Top 20 Translational Research Laboratories of the Year by Nature Biotechnology. He is president of the International Society for Vaccines (ISV) and is an elected Fellow of the American Association for the Advancement of Science. He was named one of the nation’s top 40 most influential Vaccine Scientists in 2014.

“Since his arrival at Wistar, David has tremendously expanded our research enterprise in infectious diseases and cancer, bringing to clinical testing next generation technologies for vaccine and immunotherapy development,” said Dario C. Altieri, M.D., president and CEO of The Wistar Institute and director of its Cancer Center. “Working in seamless partnership with academia, industry and philanthropic foundations, David is redefining concepts of biomedical innovation and scientific preeminence that will benefit millions.”

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Wistar Science Highlights: New Synthetic DNA Vaccine for an Emerging Infectious Disease, Combination Treatment for Therapy-resistant Melanoma Patients and New Link Between Cellular Senescence and Cancer

Written by The Wistar Institute on February 15, 2019. Posted in Featured News.

A novel, synthetic DNA vaccine developed by the lab of Kar Muthumani, Ph.D., director of the Laboratory of Emerging Infectious Diseases and assistant professor in Wistar’s Vaccine & Immunotherapy Center at Wistar, induces protective immunity against Mayaro virus (MAYV), a mosquito-borne infection endemic to South America, that has the potential to become a global emerging viral threat. Study results were published in PLOS Neglected Tropical Diseases.

MAYV infection causes fever, rash, headache, nausea, and vomiting for prolonged periods in many people and can lead to persistent and debilitating muscle and joint pain in some patients. There are no approved treatments or preventative medicines for Mayaro fever.

Immunization with the new vaccine scMAYV-E induced potent protective and MAYV-specific immune responses in mice and provided complete protection from death and clinical signs of infection in a MAYV-challenge mouse model.

“The robust immunogenicity of the scMAYV-E vaccine demonstrated here supports the need for further testing of this vaccine as a viable means to halt the spread of this virus and protect individuals at risk from MAYV disease,” said Muthumani. READ MORE

Collaborative research by the lab of Dmitry I. Gabrilovich, M.D., Ph.D., Christopher M. Davis Professor and program leader of the Immunology, Microenvironment and Metastasis Program at Wistar, and Moffitt Cancer Center has demonstrated that BRAF-targeted therapies render resistant melanoma more sensitive to the attack of killer T cells. This result, published online in Clinical Cancer Research, suggests that adoptive T cell therapy may benefit patients that have become resistant to BRAF inhibitors.

Study showed that BRAF inhibitors (BRAFi) targeting the BRAF protein, which is mutated in approximately 50% of melanoma patients, induce upregulation of a protein called mannose-6-phosphate receptor (M6PR) on cancer cells. This receptor mediates intake of the toxic substances released by killer T cells to destroy their target cells. As a consequence, increased expression of M6PR correlated with increased sensitivity of melanoma cells to the toxic activity of tumor infiltrating lymphocytes. Importantly, this effect was also seen in BRAFi-resistant cells.

The translational relevance of these observations was evaluated in a pilot clinical trial in which 16 patients with metastatic melanoma were treated with the BRAFi vemurafenib followed by adoptive T cell therapy, or infusion of tumor infiltrating lymphocytes isolated from the same patient and expanded ex vivo. The combination treatment was well tolerated and BRAFi caused a marked increase in M6PR in the patients’ tumors.

This study thus suggests that adoptive T cell therapy may be therapeutically useful for patients who experienced tumor progression on BRAFi. READ MORE

In a study published online in Nature Cell Biology, the lab of Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center, professor and co-program leader of the Gene Expression and Regulation Program, described a novel mechanism by which senescent cells release tumor-promoting molecules.

During cellular senescence, which represents a potent tumor suppressive mechanism, cells irreversibly stop dividing. At the same time, they produce a variety of inflammatory soluble molecules that can promote tumor growth, known by the name of senescence-associated secretory phenotype (SASP).

The lab investigated the role of a family of proteins called HMGAs in these processes and unveiled the dual role they play in cancer.

Researchers found that higher levels of the HMGA1 protein, as frequently found in many cancer types, result in increased production of nicotinamide adenine dinucleotide (NAD+), a cellular factor critical for metabolism and enzyme function. Higher NAD+ metabolism promotes a higher SASP and enhances the inflammatory environment around the tumor, which translated into a stimulatory effect on cancer growth and development in mouse models of pancreatic and ovarian cancers.

“It is well documented that cellular NAD+ concentrations decrease during aging and the use of NAD+ supplementation is being studied as a new preventive opportunity for aging and age-associated disorders,” said Zhang. “Our results may have far-reaching implications on this field of investigation.” READ MORE

State Funding Awarded to Wistar in Support of its Biomedical Research Training & Workforce Development Programs

Written by The Wistar Institute on February 14, 2019. Posted in Press Releases.

PHILADELPHIA — (Feb. 14, 2019) — The Wistar Institute was awarded two grants totaling more than $128,000 from the Pennsylvania Department of Labor & Industry to support the Institute’s training and workforce development initiatives in biomedical research.

The funding comes from PAsmart, an initiative outlined last year by Governor Tom Wolf to better align education and workforce development initiatives to drive economic growth, with the goal of enhancing skills and developing talent in science, technology, engineering and math (STEM), and computer science industries. Governor Wolf recently announced grants to increase apprenticeships and job training in the commonwealth.

The grants will provide funding for Wistar’s Biomedical Technician Training (BTT) Program and Biomedical Research Technician (BRT) Apprenticeship, both of which embody the Institute’s commitment to developing talents in biomedical research to support the expanding biotech industry in the Philadelphia area.

“With its longstanding community training efforts, Wistar has been a pioneer in workforce development in the biomedical sector,” said Dario C. Altieri, M.D., president and CEO of The Wistar Institute. “We are proud of our critical role and we are thrilled that the Commonwealth of Pennsylvania is investing in apprenticeships as a resource to create a highly specialized workforce for the vibrant life sciences enterprise in our region.”

The BTT Program was founded in 2000 by Wistar’s William Wunner, Ph.D., director of Academic Affairs, Outreach Education and Technology Training, in partnership with the Community College of Philadelphia. The program uniquely combines academic course work with specialized training in research laboratories, preparing community college students for new career opportunities as research assistants and technicians, and has a long successful track record in creating new job opportunities. The $60,000 pre-apprenticeship grant awarded through PAsmart to the BTT Program will provide important support to the program.

An extension of the BTT Program, Wistar’s BRT Apprenticeship is the first registered, non-traditional apprenticeship in the biomedical sciences in the country, and was formally approved by the Pennsylvania Department of Labor & Industry in 2017. By leveraging collaborations between Wistar and research partners in biotech, biopharmaceutical, and academic research settings, the program offers apprentices highly specialized technical and professional skills valued by the life sciences industry, while providing a wage as they train. The new “First Up” grant will provide the Apprenticeship funding for $68,262, which will allow for expansion of the BRT Apprenticeship each year.

“We are very grateful to the Commonwealth of Pennsylvania for investing in Wistar’s signature workforce development and training programs,” said Brian Keith, Ph.D., dean of Biomedical Studies at Wistar. “Receiving state approval for the BRT Apprenticeship last year and being able to attract state funding now demonstrate the hard work and passion that Dr. Wunner and Wistar leadership have invested over the decades, and will advance our training efforts to reach more students in the Philadelphia region.”

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer, infectious disease 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.

Combination of T Cell Therapy and Targeted Therapy as a Novel Strategy for Therapy-resistant Melanoma with Mutations in the BRAF Gene

Written by The Wistar Institute on February 14, 2019. Posted in Press Releases.

PHILADELPHIA and TAMPA, Fla. — (Feb. 14, 2019) — Collaborative research by The Wistar Institute and Moffitt Cancer Center has demonstrated that BRAF targeted therapies render resistant melanoma more sensitive to the attack of killer T cells. This result, published online in Clinical Cancer Research, suggests that adoptive T cell therapy may benefit patients that have become resistant to BRAF inhibitors.

Approximately 50% of melanoma patients carry a mutation in the BRAF protein. Targeted therapy with inhibitors of BRAF and the downstream pathway is very effective in these patients, but long-term benefits are limited due to the onset of therapy resistance. Previous studies demonstrated that BRAF inhibitors (BRAFi) positively affect the antitumor immune response mediated by T cells, and a recent small clinical trial has shown positive clinical responses in patients treated with a combination of BRAFi and adoptive T cell therapy, or infusion of tumor infiltrating lymphocytes isolated from the same patient and expanded ex vivo.

“The combinatorial approach of BRAFi and adoptive cell therapy is very promising but the mechanisms mediating this interaction have not been elucidated,” said Dmitry I. Gabrilovich, M.D., Ph.D., Christopher M. Davis Professor and program leader of the Immunology, Microenvironment and Metastasis Program at Wistar and a co-corresponding author on the study. “More importantly, we had no proof that this strategy would also benefit patients who have developed resistance to BRAFi therapy.”

Research from the Gabrilovich Lab has shown that increased levels of a protein called mannose-6-phosphate receptor (M6PR) are important for the antitumor effects of combination treatment with immunotherapy and chemotherapy or radiation therapy in different mouse models of cancer.

“We asked whether BRAFi could induce the same upregulation of M6PR and whether this effect could be exploited to potentiate the effects of adoptive T cell therapy in BRAFi-resistant tumors, for which clinical options are still very limited,” said Amod Sarnaik, M.D., associate member of the Department of Cutaneous Oncology at Moffitt and a co-senior author on the study.

Importantly, M6PR is a receptor for granzyme B, a substance produced by activated CD8+ T cells, and mediates the intake of the toxic cargo released by these killer immune cells.

The team confirmed that BRAF inhibition induces higher expression of M6PR in melanoma cells in culture. Importantly, this effect was also seen in BRAFi-resistant cells. Furthermore, increased expression of M6PR correlated with higher intake of granzyme B and increased sensitivity of melanoma cells to the toxic activity of tumor infiltrating lymphocytes.

The translational relevance of these observations was evaluated in a pilot clinical trial in which 16 patients with metastatic melanoma were treated with the BRAFi vemurafenib followed by adoptive T cell therapy with tumor infiltrating lymphocytes. The combination treatment was well tolerated, and researchers observed that BRAFi caused a marked increase in M6PR in the patients’ tumors.

This study suggests that adoptive T cell therapy may be therapeutically useful for patients who experienced tumor progression on BRAFi.

Co-authors: Co-first authors Cigdem Atay and Taekyoung Kwak, Sergio Lavilla-Alonso, Laxminarasimha Donthireddy, Vito W. Rebecca, Min Xiao, Jiufeng Tan, Gao Zhang, and Meenhard Herlyn from Wistar; Allison Richards, Valerie Moberg, Shari Pilon-Thomas, Michael Schell, and Jane L. Messina from Moffitt; Jeffrey S. Weber from New York University Langone Health.

Work supported by: National Institutes of Health (NIH) grants Melanoma SPORE P50CA168536, Melanoma SPORE P50CA174523, 5P01CA114046, 1U54CA224070, NCI-K23CA178083; department of defense grant WX1XWH-16-1-0119 (CA150619); research grants from Genentech Inc., the Donald A. Adam Melanoma and Skin Cancer Center of Excellence at Moffitt Cancer Center; the Swim Across America Foundation, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and a Leo and Anne Albert American Cancer Society Foundation Research Scholar Grant. Core support for Wistar and Moffit was provided by Cancer Center Support Grants P30CA010815 and P30CA076292, respectively. Vemurafenib was provided by Genentech Inc. and IL-2 was provided by Prometheus Laboratories Inc.

Publication information: BRAF targeting sensitizes resistant melanoma to cytotoxic T cells, Clinical Cancer Research (2019). Advance online publication.

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