Author: The Wistar Institute

Setting the Stage for Success: The Busy Life of a Graduate Student at Wistar

Written by The Wistar Institute on September 12, 2019. Posted in Featured News.

Gretchen Alicea is a graduate student at The Wistar Institute and is enrolled in the Ph.D. Program in Cancer Biology overseen jointly by Wistar and University of the Sciences (USciences). She has a lot on her plate: She is conducting exciting research for her Ph.D. thesis, has just submitted a paper for publication and is preparing to graduate next year, all the while raising two small children. Yet, she exudes energy and enthusiasm.

Born and educated in Puerto Rico and trained as a research technician in Tampa at the Moffit Cancer Center, Alicea had her sights set on entering a graduate program. Upon speaking with Wistar’s Meenhard Herlyn, D.V.M., D.Sc., professor in the Molecular and Cellular Oncogenesis Program and director of Wistar’s Melanoma Research Center, about his lab’s research, she knew Wistar was the place to be. Dr. Herlyn advised her to apply to the Wistar/USciences Ph.D. Program in Cancer Biology.

“I am passionate about cancer research and I think melanoma is a particularly exciting field because of the availability of several experimental models,” said Alicea. “So, I jumped at the opportunity to work on my Ph.D. thesis at Wistar, which is a prestigious and renowned place for cancer research.”

“Enrollment in the program is selective,” said Brian Keith, Ph.D., dean of Biomedical Studies at Wistar. “But we base our selection process on the candidate’s drive, motivation and previous lab experience more than on their grades on paper. We find that our students hit the ground running.”

Alicea was a successful candidate because she had worked in a lab as a technician and during that time, she had contributed to the publication of two papers.

“Candidates are expected to be motivated and demonstrate that in their application to the program,” said Alicea. “They must show critical thinking and have a well-thought-out idea of the particular labs they would like to join.”

Coming from a warm country and having lived in Florida, Philadelphia was Gretchen’s first approach with the Northeast winter. “I hated the cold but being accepted in the Program was worth dealing with it for sure.”

Alicea remembers the first two years as very demanding yet exciting, as students are required to take courses, apply their skills while rotating in three Wistar labs (to find the best fit) and also teach undergraduate classes.

“Even if it was intense, the experience trained me in juggling different tasks, which I think is a very valuable skill for a researcher,” said Alicea. “I think the program sets you up to be a well-rounded scientist.”

After completing her rotations, Alicea decided to stay in the lab of Ashani Weeraratna, Ph.D., in the Immunology, Microenvironment and Metastasis Program. Dr. Weeraratna helped her choose and design her own project and obtain funding for her research.

Alicea is studying the role of the melanoma microenvironment in elderly patients, focusing on fibroblasts and the changes in their cellular metabolism that favor cancer cell aggressiveness. Now in her fourth year, she is preparing to write her thesis once her paper is accepted for publication. She is very satisfied with the program and with her experience at Wistar.

“Undertaking research at Wistar means you are surrounded by high-caliber scientists and mentors, you get to work on impactful, cutting-edge projects and have access to the latest technological support,” said Alicea.

After graduation she plans to pursue an academic career and one day hopes to establish her own lab.

“Students who graduate from this program know the quality of their research, featured in high-impact publications, speaks for itself,” said Alicea. “Wistar’s reputation and being exposed to this research community also provide powerful assets to succeed.”

Major Grant Awarded to Wistar Supports Development of a Novel Therapeutic Approach for Antibiotic-resistant Bacteria

Written by The Wistar Institute on September 12, 2019. Posted in Press Releases.

PHILADELPHIA — (September 12, 2019) — The Wistar Institute has received a grant of approximately $4.6 million from the National Institutes of Health in support of innovative research to tackle antibiotic resistance.

Antimicrobial resistance (AMR) represents an expanding global public health concern. While antibiotic-resistant organisms are appearing at an alarming rate, there has been a 30-year hiatus in the development of novel classes of antibiotics for combatting these infections. Multidrug-resistant Pseudomonas aeruginosa is one of the top microorganisms on the list of priority AMR pathogens compiled by the World Health Organization.

A Wistar team led by 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 Wistar, is advancing a novel, nontraditional approach to combat multidrug-resistant P. aeruginosa, based on a synthetic DNA technology called DNA-encoded monoclonal antibodies (DMAbs). In a recent study, Weiner and colleagues developed a targeted DMAb approach for AMR and demonstrated that these DMAbs can effectively control multidrug-resistant P. aeruginosa infection in mice.

This grant will now allow for extension of these studies by providing the researchers with $4,624,553 over four years to further implement the DMAb strategy and move it forward toward clinical development.

The Weiner lab developed DMAb technology by designing genetic sequences directly encoding monoclonal antibodies into an optimized DNA platform. These gene sequences are administered in vivo to be expressed locally at the site of injection. The recipient receives a gene-encoded blueprint instructing their cells to produce the encoded monoclonal antibody specifically targeting the bacteria. DMAbs can be developed simply and quickly and are produced directly in the patient, dramatically lowering production timeline and costs associated with manufacturing of conventional antibodies; furthermore, DMAbs do not require expensive cold chain storage and are suitable for delivery in combinations.

“Engineered synthetic DMAbs represent a transformative approach to the production of biomolecules directly in the patient,” said Weiner. “We are honored to receive this funding and feel it is an important recognition of the promise of DMAbs for the growing threat of antibiotic resistance. This support will move us closer to creating an out-of-the-box tool to fight antibiotic-resistant infections that threaten the lives of thousands every year just in the U.S.”

Co-investigators on the grant are assistant professor Farokh Dotiwala, M.B.B.S., Ph.D., associate professor Daniel Kulp, Ph.D., and research assistant professor Ami Patel, Ph.D., of Wistar’s Vaccine & Immunotherapy Center. Inovio Pharmaceuticals is a collaborator on the grant.

The multidisciplinary team will work collaboratively to enhance the existing P. aeruginosa DMAb platform and develop more potent options with improved antigen binding and receptor engagement. They will be further tested in preclinical models to support translation of this DMAb approach and ultimately move it forward to human studies.

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The Wistar Institute is an international leader in biomedical research with special 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.

Role of Cancer Protein ARID1A at the Intersection of Genome Stability and Tumor Suppression

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

PHILADELPHIA — (Sept. 6, 2019) — The ARID1A tumor suppressor protein is required to maintain telomere cohesion and correct chromosome segregation after DNA replication. This finding, reported by Wistar researchers in Nature Communications, indicates that ARID1A-mutated cells undergo gross genomic alterations that are not compatible with survival and explains the lack of genomic instability characteristic of ARID1A-mutated cancers.

The ARID1A gene is one of the most frequently mutated genes in human cancers, with a mutation rate that reaches 60% in ovarian clear cell carcinoma, a disease known for its poor response to chemotherapy. ARID1A exerts fundamental tumor suppressive functions whose loss are conducive to cancer development.

“Although ARID1A is known to act as a guardian of genome integrity, cancer types with high frequency of ARID1A mutations are not typically associated with genomic instability as measured by changes in gene copy numbers,” said Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center, professor and co-program leader of the Gene Expression and Regulation Program, and lead author on the new study.

Zhang and colleagues have now shown that ARID1A is essential for telomere cohesion as it controls expression of STAG1, a component of the cohesin protein complex. In fact, ablation of ARID1A function in vitro leads to downregulation of STAG1 and, consequently, telomere defects and chromosomal alterations during cell division.

Importantly, cells with inactivated ARID1A showed reduced ability to form colonies in an assay that is used as a measure of survival of cancer cells during cell division, indicating that the chromosomal defects occurring in the absence of ARID1A are not compatible with cell survival.

“We identified a selection process that enriches for cancer cells lacking genomic instability,” said Zhang. “This may explain the apparent paradox of preserved genomic stability in ARID1A-mutated cancers.”

“Interestingly, ARID1A inactivation correlates with a poor response to cell division-targeting chemotherapy such as paclitaxel,” said Bo Zhao, Ph.D., first author of the study and a postdoctoral researcher in the Zhang Lab. “Our findings might partly explain why clear cell ovarian cancers typically respond poorly to this class of chemotherapy.”

Co-authors: Jianhuang Lin, Shuai Wu, Zhong Deng, Nail Fatkhutdinov, Joseph Zundell, Takeshi Fukumoto, Qin Liu, Andrew Kossenkov, and Paul M. Lieberman from Wistar. Lijie Rong and Cory T. Abate-Shen from Columbia University Irving Medical Center; Stephanie Jean, Mark G. Cadungog and Mark E. Borowsky from Helen F. Graham Cancer Center & Research Institute; and Ronny Drapkin from University of Pennsylvania.

Work supported by: National Institutes of Health (NIH) grants R01CA160331, R01CA163377, R01CA202919, R01CA239128, P01AG031862, P50CA228991, R01CA140652, P01CA221757, and R50CA211199; U.S. Department of Defense grants OC150446 and OC180109; additional support was provided by The Honorable Tina Brozman Foundation for Ovarian Cancer Research (Tina’s Wish) and The Tina Brozman Ovarian Cancer Research Consortium 2.0; 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: ARID1A promotes genomic stability through protecting telomere cohesion, Nature Communications (2019). 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 IMV Announce Research Collaboration to Develop New Targeted Immunotherapy Against the Common BRAF Cancer Mutation

Written by The Wistar Institute on September 4, 2019. Posted in Press Releases.

PHILADELPHIA – (SEPT. 4, 2019) – The Wistar Institute, an international leader in biomedical research in cancer, immunology, infectious diseases, and vaccine creation, and IMV Inc. (Nasdaq: IMV; TSX: IMV), a clinical-stage immuno-oncology company, announced today a collaboration to develop a targeted T-cell therapy against a common BRAF cancer mutation. This therapy will be based on peptides identified by Meenhard Herlyn, D.V.M., D.Sc., professor in the Molecular and Cellular Oncogenesis Program and director of Wistar’s Melanoma Research Center.

Mutations in the BRAF gene are the most frequently identified cancer-causing mutations in melanoma and have been identified in various other cancers, including non-Hodgkin lymphoma, colorectal cancer, thyroid cancer, and non-small cell lung and ovarian carcinomas.

“Small-molecule inhibitors of BRAF have shown to be very effective targeted cancer therapies, but have limited long-term benefit due to the onset of therapy resistance. Alternative strategies with emerging therapeutic approaches are needed for the successful long-term treatment of cancers with the BRAF mutation,” said Herlyn. “Immunotherapy could provide a more effective mechanism to target these mutations and we are excited to collaborate with IMV, as its DPX technology enables us to develop targeted T-cell therapies aimed at BRAF to test and validate this important hypothesis.”

“We are pleased to initiate this collaboration with The Wistar Institute, a world leader in biomedical research and early-stage discovery science with highly relevant expertise to our shared goals in the development of novel treatments for cancer. In particular, Dr. Herlyn has transformed the scientific understanding of stem cells as they relate to cancer and his work in melanoma serves as the basis for numerous therapies now in clinical trials or recently approved,” said Frederic Ors, IMV’s Chief Executive Officer. “We believe that cancer-driving mutations, like BRAF, which are directly involved in malignant processes and do not easily escape the immune system, represent an exciting new avenue for targeted T-cell therapies. We look forward to working with Dr. Herlyn and his team, leveraging our DPX platform to explore the therapeutic potential of this target in melanoma and other cancers.”

The project scope includes optimizing the DPX formulation with the BRAF peptides and testing the investigational T-cell therapy in the pioneering pre-clinical research models at Wistar. As part of the collaboration agreement, IMV holds an exclusive option to in-license intellectual property related to the program.

About The Wistar Institute

About IMV

IMV Inc. is a clinical stage biopharmaceutical company dedicated to making immunotherapy more effective, more broadly applicable, and more widely available to people facing cancer and other serious diseases. IMV is pioneering a new class of immunotherapies based on the Company’s proprietary drug delivery platform. This patented technology leverages a novel mechanism of action that enables the programming of immune cells in vivo, which are aimed at generating powerful new synthetic therapeutic capabilities. IMV’s lead candidate, DPX-Survivac, is a T cell-activating immunotherapy that combines the utility of the platform with a target: survivin. IMV is currently assessing DPX-Survivac as a monotherapy in advanced ovarian cancer, as well as a combination therapy in multiple clinical studies with Merck. Connect at www.imv-inc.com.

IMV Forward-Looking Statements

This press release contains forward-looking information under applicable securities law. All information that addresses activities or developments that we expect to occur in the future is forward-looking information. Forward-looking statements are based on the estimates and opinions of management on the date the statements are made. In the press release, such forward-looking statements include, but are not limited to, statements regarding the FDA potentially granting accelerated regulatory approval of DPX-Survivac. However, they should not be regarded as a representation that any of the plans will be achieved. Actual results may differ materially from those set forth in this press release due to risks affecting the Corporation, including access to capital, the successful design and completion of clinical trials and the receipt and timely receipt of all regulatory approvals. IMV Inc. assumes no responsibility to update forward-looking statements in this press release except as required by law. These forward-looking statements involve known and unknown risks and uncertainties and those risks and uncertainties include, but are not limited to, our ability to access capital, the successful and timely completion of clinical trials, the receipt of all regulatory approvals and other risks detailed from time to time in our ongoing quarterly filings and annual information form Investors are cautioned not to rely on these forward-looking statements and are encouraged to read IMV’s continuous disclosure documents, including its current annual information form, as well as its audited annual consolidated financial statements which are available on SEDAR at www.sedar.com and on EDGAR at www.sec.gov/edgar.

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Source: IMV Inc.

Investor Relations
Marc Jasmin, IMV Senior Director, Investor Relations
O: (902) 492-1819 ext : 1042
M: (514) 617-9481 E: mjasmin@imv-inc.com

Josh Rappaport, Director, Stern IR
O: (212) 362-1200
E: josh.rappaport@sternir.com

Media
Mrs. Delphine Davan, IMV, Director of Communications
O: (902) 492-1819 E: ddavan@imv-inc.com

Wistar Science is Launchpad for Creating First MERS Vaccine that Has Completed Phase 1 Human Trial

Written by The Wistar Institute on August 27, 2019. Posted in Featured News.

Using enhanced DNA vaccine technology, Wistar scientists can speed the development of vaccines for emerging diseases creating impactful countermeasures against outbreaks.

Wistar’s Drs. Kar Muthumani, David Weiner and collaborators unlocked the R&D potential of synthetic DNA vaccines to develop the first synthetic DNA vaccine for Middle East Respiratory Syndrome (MERS) in 11 months (research published in Science Translational Medicine in 2015). The vaccine entered and completed phase 1 human trials in 2017 and results were published on July 24, 2019 in The Lancet Infectious Diseases.

In 2012, the first MERS outbreak occurred in Saudi Arabia. This virus had never been seen before. Spread through camels and bats, MERS is a highly infectious respiratory disease predominant in the Middle East. Fast forward to 2015, when an individual who had contracted MERS returned to South Korea from the Middle East. This led to a South Korean outbreak that resulted in 186 confirmed cases and 38 deaths. The outbreak affected 24 hospitals, led to the temporary closure of more than 2,000 schools, and had a significant impact on the South Korean economy.* In 2018, The World Health Organization (WHO) listed MERS as a potential public health emergency in the annual review of the Blueprint list of priority diseases.

“MERS was such a new emerging infectious disease that no research on it had been done before the 2012 outbreak,” said Muthumani. “But I knew MERS was similar to Severe Acute Respiratory Syndrome (SARS), so I gathered knowledge of the 2001/2002 SARS outbreaks in China/Asia to guide how we would create a MERS vaccine.”

Wistar’s Vaccine & Immunotherapy Center is currently leading the charge for the development of multiple synthetic DNA-based vaccines. A synthetic DNA MERS vaccine works like this: An injection of a simple DNA plasmid tells the body to generate a foreign protein derived from the pathogen, which then causes the immune system to respond and destroy the MERS virus if it were to infect the body.

Though Muthumani and his team had to start from scratch because no reagents were available to design and test vaccine efficacy, Muthumani’s knowledge of SARS — a coronavirus related to MERS — was the blueprint from which they created reagents, a pseudo-virus and developed immune responses to multiple related strains of MERS.

There are several conceptual advantages to synthetic DNA vaccines compared to other vaccine platforms. DNA vaccines possess virtually no risk of causing disease since no infectious agents are injected into the body. DNA vaccines have had an exceptional safety profile in numerous clinical trials over the last 20 years. Additionally, new technologies allow DNA vaccines to be designed and manufactured quickly and inexpensively, which makes them an ideal platform for dealing with rapidly emerging pathogens that develop in underdeveloped regions of the world.

“With how fast pandemics spread in this day and age, this technology to swiftly craft a vaccine against new threats could be revolutionary,” said Muthumani.

*Centers for Disease Control and Prevention

Beyond Vaccines: Looking to Cures for Infectious Diseases

Written by The Wistar Institute on August 22, 2019. Posted in Featured News.

New infectious diseases are on the rise: In 2015 and 2016, there was an upswing in Zika outbreaks in the U.S., and the virus still impacts many parts of the world. The Ebola epidemic in the Democratic Republic of Congo (DRC) is the second largest in history, according to the CDC. HIV remains an incurable disease.

All of these epidemics beg one question that members of Wistar’s Vaccine & Immunotherapy Center are interested in solving: can we create a cure for infectious diseases?

In particular, Kar Muthumani, Ph.D., assistant professor in Wistar’s Vaccine & Immunotherapy Center and director of the Laboratory of Emerging Infectious Diseases, is pursuing whether we can develop antibody therapeutics to help people recover from infection.

“Historically, vaccines have been our answer to global disease prevention but look at Ebola in the DRC — when an outbreak has already started, people with the disease need a therapeutic not a preventative answer,” said Muthumani. “In my lab at Wistar we are focused on therapeutics that could be given to anyone who comes down with symptoms; patients would receive a blood test to confirm the type of disease and take the therapy for that specific disease.”

Muthumani’s expertise is in design and creation of synthetic DNA-based vaccines and therapeutics. His work crosses over between infectious diseases and cancers. He’s actively working on Zika virus, Mayaro virus, chikungunya, Middle East respiratory syndrome (MERS), Nipah virus, Junín virus (JUNV), Crimean-Congo hemorrhagic fever (CCHF), dengue virus, and HIV.

Muthumani is strongly committed to antibody therapy as a strategy to provide relief for emerging disease situations. Antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAb) to bind to specific cells or proteins that will prevent infection and/or stimulate an individual’s immune system to attack the harmful cells. He is currently working with partners to characterize immune cells and antibodies from survivors of South India’s 2018 Nipah outbreak in Kerala, with the goal of engineering these antibodies, leveraging synthetic DNA technology and delivering them directly to patients. These antibody therapies would be ready to attack the virus and boost the body’s ability to fight infection. The goal is to provide an immediate protection while the body builds a long-lasting immune response to immunization.

Just two floors away at Wistar is the lab of Luis J. Montaner, D.V.M., D.Phil., director of the HIV-1 Immunopathogenesis Laboratory and HIV Program leader, who is also focused on a cure, but for another infectious disease – HIV/AIDS.

There are approximately 37 million people living with HIV worldwide and 21.7 million are receiving antiretroviral therapy (ART), according to the World Health Organization. ART suppresses the HIV virus and reduces disease progression, helping people with HIV live longer and preventing onward transmission. However, ART does not eliminate infection and has to be taken daily for life, thus the priority to move HIV cure research forward.

Montaner’s 20+ years of HIV/AIDS research at Wistar has propelled him into his largest research project: the BEAT-HIV Delaney Collaboratory. He oversees a consortium of more than 80 top researchers from academia, government, nonprofit, and industry working to define the most effective way to combine immunotherapy regimens to advance new cure-directed efforts against HIV through new preclinical research and clinical trials. Their work centers on investigating where HIV hides after therapy and testing novel clinical strategies ultimately aimed at a cure that eliminates the hidden virus.

The consortium has three important goals, including two first-in-class clinical HIV cure-directed studies:

1) identifying where and how HIV hides in the body of people on antiretroviral therapy to better determine new strategies to kill the virus;
2) stimulating the innate immune system to be stronger against HIV, combining a medication called pegylated interferon alpha 2b, which may help control viruses, and potent antibodies that can neutralize HIV; and
3) introducing new “killer T cells” by bringing together two promising gene therapy strategies, independently tested in humans, with the goal of engineering, growing and administering killer T cells that are uniquely empowered to find and kill HIV-infected cells.

“Lifelong stigma, economic burden on society, strain on healthcare resources, and sheer toll on human life across the globe makes finding a cure a top priority,” said Montaner. “Together, we’re building on our teams’ extensive and established efforts to move forward and make those next transformative steps that will bring us closer to an HIV cure within our lifetime.”

Wistar scientists are dedicated to the design and creation of vaccines and therapies to stem the tide of the global burden of disease. Research is one major piece of an integrated push across communities, governments and countries for the best global health outcomes.

Scientist Luis Montaner smiles in a Wistar lab

Repeated Semen Exposure Promotes Host Resistance to Infection in Preclinical Model of HIV

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

PHILADELPHIA — (Aug. 21, 2019) — Contrary to the long-held view that semen can only act as a way to transmit HIV-1 from men to women, scientists at The Wistar Institute and the University of Puerto Rico found that frequent and sustained semen exposure can change the characteristics of the circulating and vaginal tissue immune cells that are targets for infection, reducing the susceptibility to a future infection. This finding, published in the journal Nature Communications, also provides a potential explanation as to why a small number of female sex workers worldwide continue to test negative for infection despite continuous high-risk sexual activity.

Research previously reported by the laboratory of Luis J. Montaner, D.V.M., D.Phil., the Herbert Kean, M.D., Family Professor and director of the HIV-1 Immunopathogenesis Laboratory at Wistar’s Vaccine & Immunotherapy Center, together with investigators at the University of Puerto Rico, showed in a 2015 paper how continued semen exposure in female sex workers resulted in changes in the cervicovaginal tissue that predicted an increased resistance to HIV infection. The current study directly addressed if semen could be a factor in resistance.

“While HIV infection has been with us for more than 30 years, this is the first study that describes how semen exposure over time could result in local tissue changes that limit HIV infection in humans,” said Montaner, who is the lead author of the new study. “Apart from defining a new factor that may regulate HIV transmission, this unexpected finding could directly impact the design of future HIV vaccine studies that commonly recruit female sex workers. Currently, condomless sex is assumed to only promote the likelihood of infection. Our observation, however, raises the hypothesis that frequent semen exposure may potentially reduce HIV transmission.”

Edmundo N. Kraiselburd, Ph.D., professor at the University of Puerto Rico (UPR), co-directed this research project and supervised the use of non-human primates (NHP) from the Caribbean Primate Research Center. NHPs are a principal pre-clinical research model used to test prophylactic anti-HIV interventions.

“This research clearly shows the valuable information the macaque model can provide when used to study what may determine HIV infections in humans,” said Kraiselburd.

In the study, animals were exposed to semen twice a week over 20 weeks with or without inactivated particles of the simian immunodeficiency virus (SIV is an HIV-like virus that infects primates and causes a disease similar to AIDS); after this conditioning period, they received low-dose intravaginal SIV challenges.

Semen-exposed animals showed a 42% decrease in the risk of infection. Scientists analyzed specific markers of immune activation in the cervicovaginal microenvironment and in the bloodstream. On circulating CD4+ cells, semen conditioning was associated with lower expression of the CCR5 receptor, which acts as a binding site for HIV to enter its host cells, supporting the observation of a lower susceptibility to SIV vaginal challenge. Furthermore, semen-conditioned animals had higher levels of the CCL5 cytokine, a natural HIV-suppressive factor, in the cervicovaginal compartment in response to SIV challenge.

Additionally, repeated semen exposure resulted in elevated cervicovaginal tissue levels of antiviral factors such as MX1, which also positively correlated with levels of IFN-epsilon. IFN-epsilon, which can be induced by semen and protects human cells from bacterial and viral pathogens, has direct anti-HIV properties and was described to be induced in tissues from sex workers in association with condomless sex.

Of note, semen-treated animals that remained uninfected after exposure to low viral amount became infected when subsequently challenged with high doses of virus, confirming that they were still susceptible to infection and that repeated semen exposure provides only partial protection and does not block HIV infection.

“Importantly, we show that semen exposure can promote host resistance but does not protect against infection,” said Montaner. “Therefore, our data do not change the fact that prevention methods, such as condom use and PrEP (pre-exposure prophylaxis) remain our best strategies to prevent infection.”

Co-authors: first author Shaheed Abdulhaqq, Jocelin Joseph, Livio Azzoni, Xiangfan Yin, Megan Wise, David Weiner, and Qin Liu from Wistar; Melween Martinez, Idia V. Rodriguez, Stephanie M. Nichols, Carlos Sariol, and Edmundo N. Kraiselburd from University of Puerto Rico; Guobin Kang and Qingsheng Li from University of Nebraska; David Beaumont and Georgia D. Tomaras from Duke University; Andrea Foulkes from Mount Holyoke College, South Hadley, MA; Jan Münch and Frank Kirchhoff from Ulm University, Germany; Christos Coutifaris from University of Pennsylvania; and Preston A. Marx from Tulane University.

Work supported by: National Institutes of Health (NIH) grants R01 AI084142, R01 AI094603, P40 OD012217 and T32 AI070099; the Robert I. Jacobs Fund of the Philadelphia Foundation; the Kean Family Professorship; the Penn Center for AIDS Research, the Duke Center for AIDS Research; and the DFG (German Research Foundation). Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30 CA10815.

Publication information: Repeated semen exposure decreases cervicovaginal SIVmac251 infection in rhesus macaques, Nature Communications (2019). Online publication.

Other media coverage below:

Repeated semen exposure promotes host resistance to infection in preclinical HIV model
Science Daily
August 21, 2019

Semen may help prevent HIV infection in women: study
New York Post
August 21, 2019

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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.

Why Don’t We Respect Bacteria? First Symposium on Bacterial Resistance at Wistar

Written by The Wistar Institute on August 13, 2019. Posted in Featured News.

There is an antibiotic crunch happening globally and to address this stalemate, Wistar hosted its first gathering of top scientists working to combat antibiotic resistance.

The recent U.K. Review on Antimicrobial Resistance outlines the growth in this problem. It predicts an increase in deaths from antimicrobial resistant (AMR) infections from 700,000 per year today, to approximately 10 million per year over the next 30 years, and that the global economic cost of AMR could reach $100 trillion dollars by 2050.

Bacterial infections are increasingly resistant to our world collection of antibiotics, which were once our best line of defense. Many of these drugs are no longer effective for treating those same infections, and instead are leading to increasingly drug-resistant diseases, even “superbugs.”

Wistar recently held a scientific symposium to bring experts together and share in the latest discoveries to combat AMR. The Gram-negative Bacterial Resistance Symposium, supported by Pfizer Inc., was one of the few academic-industry conferences exchanging and exploring new ideas to fighting AMR. It featured leaders from across the nation, including Wistar’s very own Drs. David Weiner, Farokh Dotiwala and Ami Patel who spoke to this “post-antibiotic” era we have entered, and provided a vision of new approaches to head off this growing concern.

Bacteria – A Global Threat

Bacteria are classified into gram-positive and gram-negative, with gram-negative being more resistant to antibiotics due to a thicker, protective outer membrane as well as containing many internal “pump” proteins that recognize and pump out toxic drugs, allowing them to escape the effects of many current antibiotics. Of the top 10 global AMR threats, seven are gram-negative organisms. The top three most deadly threats are gram-negative infections.

“The World Health Organization lists antibiotic resistance as one of the biggest threats to global health,” said Weiner, executive vice president, director of the Vaccine & Immunotherapy Center and W.W. Smith Charitable Trust Professor in Cancer Research at Wistar, during his opening address. “This topic is central now. For your attendance you have an assignment: We can no longer follow what has been done before, but must lead with new approaches and strategies against gram-negative pathogens!”

Throughout the day, researchers shared challenges and solutions to better understand multidrug-resistant strains like Acinetobacter baumannii (Iraqibacter), Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli (E. coli), malaria, salmonella, shigella, and gonorrhea.

Presenters like Dotiwala, assistant professor in the Vaccine & Immunotherapy Center at Wistar, are thinking outside the box to find new approaches to getting inside gram-negative bacteria and successfully delivering a new type of drug.

Dotiwala is working on a novel class of antibiotics that would target a niche in bacterial enzymes to kill the bacteria and activate the immune system. His research will lead to highly specific antimicrobial strategies against antibiotic-resistant strains as well as promising anti-cancer immunotherapies.

Patel, a research assistant professor in Wistar’s Vaccine & Immunotherapy Center and a collaborator with the Weiner lab, is applying her research developing synthetic DNA vaccines and synthetic DNA-based monoclonal antibodies (DMAbs) to numerous infectious diseases with the hope of moving new therapies forward.

Patel discussed how the synthetic DNA platform has the potential to prevent and improve recovery from AMR infections of Pseudomonas aeruginosa, an opportunistic organism that is a serious threat in immunocompromised people. In a hospital setting, it is easily spread and can cause pneumonia, blood infections and urinary tract infections.

Upon closing the symposium with a panel discussion, Dr. Paul Offit, director of the Vaccine Education Center and attending physician in the Division of Infectious Diseases at Children’s Hospital of Philadelphia, said “The post antibiotic era looks like the pre-antibiotic era.”

He then held up the 1925 book Arrowsmith by Sinclair Lewis, a fictional story about a phage discovery that cures bubonic plague and saves a South American community. Offit asked the panelists what about bacteriophages as a commercial product are holding us back, at least as a personalized approach for patients with highly intractable diseases. All the panelists agreed that the challenges are great and numerous but, as this day showcased, many promising approaches are underway.

Dr. Sanjay Ram, professor of Medicine at the University of Massachusetts Medical School, showed promising data targeting N. Gonorrheae with designed antibodies and DNA-encoded monoclonal antibodies and suggested they may be game changing. Dr. Daniel Zurawski, chief of Pathogenesis and Virulence at Walter Reed Army Institute of Research, discussed antibody technologies that may be of particular importance for AMR as they can be combined with traditional antibiotics and tested quickly to limit resistance. Dr. Kathrin Jansen, SVP and head of Vaccine Research & Development at Pfizer Inc., commented on vaccine approaches and how researchers should think in terms of personalized treatments and how new immune tools may be very useful.

Emily Kramer-Golinkoff made an impassioned presentation to the attending researchers that bacteria resistance constitutes the single greatest threat to the Cystic Fibrosis (CF) community. She has advanced-stage CF and is the founder of Emily’s Entourage, a nonprofit that brings together research, patient, pharmaceutical, and biotech communities to raise funds and accelerate R&D development of therapies to benefit patients who carry nonsense mutations and do not respond to current and breakthrough drugs.

“I feel the pressure of time with every single breath I take,” said Emily. “I speak on behalf of myself and every single person fighting this disease. Our lives, our futures are on your shelves, in your hands, and you are the brilliant researchers uniquely capable of developing and shepherding our life-saving therapies through the pipeline and into clinic in record speed.”

“There is always a human cost to medical breakthroughs, and we pay the highest human cost when we don’t take on the challenges,” concluded Offit.

Symposium on Gram-Negative Bacterial Resistance

Dr. Kazuko Nishikura: the RNA Explorer

Written by The Wistar Institute on August 8, 2019. Posted in Featured News.

Nishikura has been a pillar of Wistar science for the past 37 years with a career overlapping with the rise and expansion of the RNA biology field, which explores the alternative functions of RNA in the cell, besides carrying the genetic information from DNA to proteins. Her foray into research happened at a time when scientists were only beginning to understand the function of RNA and its molecular mechanisms; she would end up contributing fundamental knowledge to the field.

Nishikura discovered the process of RNA editing, an important mechanism of genetic regulation. Her scientific journey has taken her on to explore several aspects and functions of RNA editing and its interplay with other molecular pathways.

Passion for Science Sparks

Born and educated in Japan, Nishikura was encouraged by her high school science teacher who recognized her scientific talent. She obtained her PhD at Osaka University and pursued postdoctoral training at the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge, England, and Stanford University, two of the birthplaces of molecular biology.

Photos of those times hang from the wall in her office, memories of a cherished past, and portray some very famous scientists who left their mark in history and in Nishikura’s career: Nobel Prize winners Max Perutz, Ph.D., who discovered the structure of hemoglobin and was her doctoral thesis advisor, and John Gurdon, Ph.D., whose work on reprogramming mature cells to stem cells laid the foundation for major advances in cloning and stem cell research.

Nishikura spent two very formative years in his lab in Cambridge as a postdoctoral fellow, before moving to Stanford to work with another outstanding mentor, Roger Kornberg, Ph.D., also a Nobel laureate, who described how genetic information is passed from DNA to RNA.

Training with great minds of the time was the fertile scientific soil of her education as a scientist. Nishikura absorbed their intellectual curiosity and learned how to properly follow the scientific method as part of her training. “I consider myself very lucky for having had a chance to observe in person how those big scientists addressed important biological questions,” she said.

An Expanding Field of RNA Biology

RNA biology became Nishikura’s main research interest, which she has continued to cultivate throughout her career. It was a nascent field, rapidly expanding with fundamental discoveries, but so many questions were still unanswered.

However, at the time when she joined Wistar as an assistant professor, the Institute was mainly invested in cancer biology. Oncogenes were protagonists on the cancer research scene and Wistar scientists were pursuing seminal studies on chromosomal alterations, demonstrating their causative role in leukemia.

Nishikura was drawn into this line of investigation until the end of the 80s, when a paper by a former MRC colleague came out and described a mysterious biological activity that appeared to unwind double stranded RNA, which immediately caught Nishikura’s attention.

“I couldn’t resist looking into it,” she said. “For some time it was my pet project; no study section would believe in it and it was very risky too.”

That didn’t discourage her, and she kept pursuing the investigation with the resources she could spare from her other projects on oncogenes, which had much more success in securing funds for her lab.

“When you find something unusual you have to follow it,” said Nishikura. “Pursuing something unique will make you stand out from the crowd.”

This has been her favorite piece of advice for the young scientists training in her lab. “It’s sad and unfortunate that the current climate of high competition for funding pushes young independent investigators away from basic science. They hesitate to embark in risky projects, but these are often the source of breakthroughs.”

Nishikura considers herself fortunate to have had big opportunities that gave her the resources and the support to both follow her scientific interest and, at the same time, establish herself as a successful scientist, even though as a young investigator she wasn’t particularly focused on cultivating her academic career.

“I was only after my scientific questions and was content to just do my work and search for the answers,” she said. “In retrospect, I was probably naïve, even a little foolish. I didn’t worry much about problems and setbacks. This simplified my decision-making process and helped me stick to it.”

Thanks to her determination, Nishikura was able to secure her first grant on RNA editing when she found the gene responsible for the process. The rest is history.

“In the early 90s, RNA editing was a very new concept, with only two or three labs chasing it,” said Nishikura. “Today, it’s a large field with dozens of labs. It’s very satisfying to look back and see that I contributed to opening that path.”

The institutes where she trained put her on the right track and equipped her with a successful approach to science, then Wistar was the ideal landing ground to grow and establish herself. “Being at Wistar is a great asset, because of our collaborative environment and vocation of always being at the forefront of new trends and technologies,” said Nishikura. “It has helped substantially when I came across new themes and needed support to acquire different expertise or catch up with new develoments.”

Nishikura’s passion and curiosity are unchanged and she still finds great inspiration in science. In 2017, she successfully renewed a large federal grant that had continuously supported her work on RNA editing for 26 years, with a proposal to investigate a novel function she had recently discovered.

Outside the Lab

Meanwhile, when not in her lab, Nishikura cultivates other “side projects.”

She enjoys traveling the world, especially to places that are interesting from a biological point of view. She recently visited the Galapagos Islands and Antarctica and went on a safari in Africa. The exploration component of such trips resonates with her scientific mind.

“I love going to music concerts too,” she said. “Whenever I go to Europe for conferences, I try to catch the opera or a classic music concert.” That’s not to say that she doesn’t enjoy some good classic rock. “I’ve recently seen Eric Clapton, the Rolling Stones and Paul McCartney.”

At home, Nishikura is an experienced cook, specializing in many types of cuisine. She enjoys cooking for friends and neighbors. “I like cooking because I’m a foodie and because it takes method and creativity, just like science.”

These days, she’s been making a tasty and healthy beet salad. She will gladly share the recipe.

In the photo, Dr. Nishikura with the group of John Gurdon at the MRC Laboratory of Molecular Biology at the University of Cambridge, England. Courtesy of Dr. Nishikura.

Finding Cancer Early to Save Lives

Written by The Wistar Institute on July 24, 2019. Posted in Featured News.

Early diagnosis and screening are the bedrock for addressing cancer in a timely fashion to improve patient survival, yet laboratory diagnostics are lagging behind and so far, are limited to a few specific biomarkers for several malignancies.

Wistar scientists are advancing innovative research and discovering new biomarkers that may be useful for the development of simple, highly specific and sensitive diagnostic tests that could be used to detect cancer in its early stages, when the chances of successful treatment are significantly higher.

Lung Cancer

Symptoms of lung cancer, the primary cause of cancer-related deaths worldwide, do not appear until the disease is advanced and likely untreatable, and adequate early detection methods are scarce.

In the past decade, advances in imaging technologies have reduced mortality by 20% among high-risk individuals. However, these techniques are not specific enough to distinguish between benign and malignant lung nodules, especially the smallest ones, which are particularly challenging to diagnose and not easily accessible for further analysis. As many as 96% of these nodules prove to be false positives when analyzed histologically after invasive surgical procedures.

The development of alternative non-invasive approaches to assess these difficult-to-diagnose nodules is a critical goal in pulmonary medicine. Such techniques would also be useful to identify at-risk individuals who would benefit from imaging follow up.

Research by Louise C. Showe, Ph.D., professor in the Molecular & Cellular Oncogenesis Program at Wistar, led to the identification of a panel of biomarkers circulating in the blood that could help detect lung cancer in high-risk patients using gene expression analysis. Studies so far have shown that this strategy is both highly sensitive and specific in distinguishing cancerous nodules from benign nodules.

Dr. Showe’s research program began in 2004 and was originally supported by funds from the Pennsylvania Department of Health through the tobacco settlement CURE Program. Further support was provided by OncoCyte Corp., and most recently by a multi-year grant from the Early Detection Research Network (EDRN), an initiative of the National Cancer Institute (NCI) that supports collaborative efforts to accelerate the translation of biomarker information into clinical applications. In addition, generous philanthropic partnerships have been forged via the Wistar Science Discovery Fund in support of our lung cancer biomarker development.

OncoCyte Corp. has exclusively licensed the lung cancer biomarker technology from Wistar and is working to complete clinical validation studies of the confirmatory lung cancer diagnostic test. In parallel, Dr. Showe is continuing to investigate new unique gene expression signatures that may be useful in the diagnosis and prognosis of lung cancer.

Glioblastoma

The Showe lab is also working on creating a molecular test for the subtyping and stratification of patients diagnosed with glioblastoma, the most common and deadly type of primary malignant brain cancer in adults, that is in urgent need for assessing the response to new therapy-directing tools.

There is no known cure for glioblastoma and patients often succumb to the disease within one to two years of diagnosis. Unfortunately, glioblastoma is a complex tumor type with many different subtypes that may respond differently to various forms of cancer treatment. When patients get diagnosed, there is no treatment choice. Dr. Showe and colleagues are trying to change that, recognizing that grouping patients by subtype is an important first step for clinicians to identify and for pharmaceutical companies to develop more effective treatment strategies. Wistar is among a few leading institutions that specialize in brain tumor research and are working towards this goal.

The Wistar spin-out ISOMA Therapeutics, LLC., is advancing a glioblastoma-subtyping technology based on jointly owned patent applications of Wistar and The University of Pennsylvania. The company is developing the subtyping assay as a companion diagnostic to help direct the use of personalized therapies for glioblastoma patients.

Ovarian cancer

Another critical area of unmet need for sensitive and specific diagnostic tools is in the field of ovarian cancer – the most lethal of all gynecological malignancies, for which early diagnosis makes a huge difference in terms of survival. In fact, when ovarian cancer is caught early, five-year survival is close to 90%, a percentage that plummets to less than 30% if patients are diagnosed after the cancer has spread. Unfortunately, most ovarian cancer cases are diagnosed too late, because the disease tends to be asymptomatic at earlier stages and the ovaries are difficult to access by imaging or other minimally invasive methods.

In addition to physical examination and ultrasound imaging, measurement of elevated serum levels of a cancer antigen called CA125 helps primary care physicians manage patient treatment after ovarian cancer has been diagnosed by other methods. However, there are no FDA-approved ovarian cancer diagnostic tests available to detect cancer prior to the onset of symptoms.

Wistar’s David Speicher, Ph.D., professor and co-leader of the Molecular & Cellular Oncogenesis Program, and his team have identified a group of novel biomarkers for detecting ovarian cancer, including CLIC1 and CLIC4, that are found both in cancer tissue samples and in the patients’ blood and are common to all the subtypes of ovarian cancer. His lab has shown that when ovarian cancer tissue is stained by antibodies to CLIC1 and CLIC4, they appear to be complementary to CA125. As these proteins have been detected in blood from cancer patients at higher levels than in non-cancer controls, these proteins might show improved diagnostic sensitivity and specificity compared with CA125 alone.

Dr. Speicher is interested in combining these new biomarkers with known ovarian cancer biomarkers including CA125 and HE-4, another FDA approved biomarker, to increase the breadth and depth of patient screening. Research to develop robust multi-plexed assays to support this initiative are underway in his laboratory.

All of these research efforts tell us one thing: when it comes to cancer, understanding the present helps predict the future to define the most effective course of action and improve survival.