Author: The Wistar Institute

Dr. Anthony Fauci and Philadelphia FIGHT’s Jane Shull Receive Wistar Legacy Award at 25th Anniversary of Jonathan Lax Memorial Lecture

Written by The Wistar Institute on October 14, 2021. Posted in Press Releases.

PHILADELPHIA—(October 14, 2021)—The Wistar Institute is proud to announce Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); Jane Shull, chief executive officer of Philadelphia FIGHT; philanthropist Ken Nimblett; Philadelphia Foundation and the Robert I. Jacobs Fund; and Philadelphia FIGHT will be honored at the Wistar Legacy Awards, a celebration of 25 years of continuous HIV research collaboration on Thursday, October 28 from 5:30 to 7:45 p.m.

Fauci will also deliver the 25th Annual Jonathan Lax Memorial Lecture at this virtual, Wistar-hosted event. Fauci’s lecture highlights research advances and the NIH’s approximately 75 percent increase in HIV cure-directed funding made in 2021, equaling approximately $53 million annually over the next five years. Other guest speakers include David Fair, HIV/LGBTQ activist and founder of Lavender Health (now the Mazzoni Center) and the AIDS Activities Coordinating Office; Ronda Goldfein, Esq., activist and executive director of the AIDS Law Project of Pennsylvania; and former Philadelphia mayor Reverend Doctor W. Wilson Goode, director and CEO of the Amachi Program mentoring children with incarcerated parents.

Focused on developing HIV/AIDS treatment strategies and moving research towards an HIV cure, Luis J. Montaner, D.V.M., D.Phil., Herbert Kean, M.D., Family Professor, leader of the HIV Research Program at The Wistar Institute, and co-principal investigator of the BEAT-HIV Delaney Collaboratory, recognizes how a 25 year joint endeavor with the support of all Legacy Award recipients has grown into a global academic-industry program bringing together scientists, advocates, clinicians, and people living with HIV in and out of Philadelphia.

“The Wistar Legacy Awards recognize 25 years of continued teamwork that has resulted in high-impact research advances, community engagement, and a true hope for a day that HIV will be cured,” said Montaner. “What started with local efforts centered in research supported by the NIH, philanthropic efforts including the Philadelphia Foundation, and local community engagement through Philadelphia FIGHT, has now grown into a large global network, and a center of excellence for cure-directed research for the benefit of people living with HIV.”

“It is a special moment for Wistar to honor the work accomplished with our collaborators, where for more than 25 years we have focused on developing a global scientific strategy for HIV cure research,” said Dario C. Altieri, M.D., Wistar president and CEO, director of The Wistar Institute Cancer Center and the Robert and Penny Fox Distinguished Professor. “This is a unique opportunity to share our global leadership and impact on HIV research—which started right here in Philadelphia—and is a testament to our scientific strengths and culture of collaboration.”

The Jonathan Lax Memorial Lecture was established by The Wistar Institute and Philadelphia FIGHT after Mr. Lax’s death to honor his legacy by bringing distinguished speakers to a lay audience. Past speakers have included luminaries in the HIV/AIDS field such as Françoise Barré-Sinoussi, Ph.D., emeritus professor at the Institut Pasteur, David D. Ho, M.D., professor of microbiology and immunology at Columbia University, and Paul Farmer, M.D., Ph.D., Harvard Medical School.

The Lecture honors Jonathan Lax, President of the Board of Philadelphia FIGHT, who died from complications of AIDS in 1996. Mr. Lax, a successful businessman, was a leading advocate for bringing information directly to people living with HIV and their families. He devoted personal resources throughout his life to helping people to learn how to make decisions that would affect their health care as a person living with HIV. In the pre-internet era, Mr. Lax helped FIGHT sponsor many public forums to assure that people living with HIV/AIDS had access to up-to-date information delivered by recognized specialists.

Editor’s Note: All awardees including Anthony Fauci, M.D., will receive the Wistar Legacy Award virtually. For more information or to cover the event, contact Darien Sutton at 215-8702048 or dsutton@wistar.org.

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

BEAT-HIV Delaney Collaboratory is part of an international consortium of more than 80 top HIV researchers from academia, industry, government, and nonprofit sectors working toward an HIV cure. The Collaboratory is leading three advanced trials to define effective ways to combine immunotherapy regimes towards a cure. BEAT-HIV.org

Philadelphia FIGHT is a Federally Qualified Health Center (FQHC) offering HIV treatment and primary care to people living with HIV/AIDS and those at high risk, as well as community education and outreach programs on HIV, Hepatitis, and other topics impacting public health. During the COVID-19 pandemic, FIGHT has provided no barrier, walk-up COVID testing to over 13,000 people in low income neighborhoods of Philadelphia, and partnered with ten community based organizations to bring COVID vaccines to these communities.

Philadelphia Foundation, founded in 1918, strengthens the economic, social and civic vitality of Greater Philadelphia. It grows effective philanthropic investment, connects individuals and institutions across sectors and geography, and advances civic initiatives through partnerships and collaboration. A publicly supported foundation, the Philadelphia Foundation manages more than 1,000 charitable funds established by its donors and makes over 1,000 grants and scholarship awards each year. To learn more visit www.philafound.org.

(left) Dr. Louise Showe works with a young scientist in the lab. (right) Dr. Andrew Kossenkov

Powering Cancer Research

Written by The Wistar Institute on October 4, 2021. Posted in Featured News.

Wistar’s scientific accomplishments could not be achieved without the support of our donors who recognize our research strengths, share our vision and are committed to tackling disease, improving human health and answering the most pressing scientific questions.

Dr. Jerry Francesco’s support is behind the latest developments in the cancer research of Dr. Louise Showe, professor in the Molecular & Cellular Oncogenesis Program of The Wistar Institute Cancer Center.

Dr. Showe is helping advance the development of a blood-based test to detect cancer at an early stage in nonsmokers with no family history of lung cancer as well as people with an increased risk, as early detection makes a difference for this most hard-to-treat cancer. Dr. Francesco learned about Dr. Showe’s work in 2019, and since then has been an essential part of making a lung cancer early diagnosis test a reality.

“The potential of this project to develop a clinical, non-invasive test based on blood gene expression is incredible,” said Showe. “There are a number of possibilities for the project including using this test to diagnose lung cancer in at-risk populations. It could also be used as a follow up test after treatment to monitor cancer recurrence. And further along in development, it could even be a test for screening the general population to help in early detection.”

Dr. Showe collaborates closely with Dr. Andrew Kossenkov, assistant professor in the Vaccine & Immunotherapy Center and member of the Gene Expression & Regulation Program. In 2007, Dr. Kossenkov started as a postdoctoral fellow in the Showe lab where the lung cancer diagnostic project quickly became his main focus for years to come. Dr. Kossenkov is now the scientific director of the Bioinformatics Facility.

“This is a very exciting project of great proportion and importance with the final goal of making a non-invasive lung cancer diagnosis from blood,” said Kossenkov. “Besides great clinical down-the-road impact, it was a technically and logistically complex endeavor, and we had to go through multiple iterations and approaches during the span of the project. That was and continues to be an exciting time and helped me to increase my expertise in the field tremendously.”

Because of donors like Dr. Francesco, Wistar scientists see the fruits of their research move forward in directions that are visionary and out of the box. Philanthropic support also gives researchers a leg up to gather the data needed to apply for large federal grants.

Wistar’s Science Discovery Fund connects philanthropists and scientists together to solve some of the biggest issues in cancer and infectious disease. It is the vehicle through which the donor community can learn about and support the highest-risk, potentially high-reward research taking place. Side by side with researchers, they move discoveries into future diagnostics or drug targets that help scientists translate basic discoveries into next-generation vaccines and medicines.

We spoke to Dr. Francesco about Dr. Showe’s work and his contributions that helped her advance a lung cancer diagnostic for one of the most common causes of cancer deaths in men and women worldwide,1 accounting for 2.1 million new cases and 1.8 million deaths in 2018.2 Twenty percent of those U.S. deaths were nonsmokers who may have smoked less than 100 cigarettes in their lifetime or might have been genetically predisposed or driven by a molecular abnormality or change.

Dr. Francesco wants people to know that Wistar scientists are a highly committed team that possesses a broad range of scientific interests and cutting-edge expertise, with an aim toward practical solutions to disease.

“I think Wistar research is the finest in the country, if not the world,” said Dr. Francesco. “Dr. Showe’s research is of immense interest because of the sad state of affairs in early diagnosis of lung cancer and for the hope of developing simple and readily available tests for this terrible disease. I only wish such tests were available for my beloved wife Lucille who passed from lung cancer. I hope that my philanthropy will help speed the early diagnosis of lung cancer so that eventually such tests can be used by family physicians in their practice. I am happy to play a small role in this project.”

Sources:

1 World Health Organization Cancer Fact Sheet, 2018
2 Source: Yale Medicine;

Our Educational Partnership with Leiden University Medical Center

Written by The Wistar Institute on October 1, 2021. Posted in Featured News.

Throughout its history, Wistar has successfully cultivated strategic relationships to accelerate the development of its discoveries toward the clinic. Recognizing that the potential of scientific discovery in biomedical research extends well beyond our borders, The Wistar Institute has recently expanded our international graduate student and post-doctoral training programs in immunology, cancer research and vaccine biology.

In the fall of 2019, the Wistar-Schoemaker International Postdoctoral Fellowship was launched in partnership with Leiden University Medical Center (LUMC) in the Netherlands. This postdoctoral training program brings LUMC graduates to Wistar for their postdoctoral training under the mentorship of a Wistar faculty member. The Wistar-Schoemaker Postdoctoral Fellowship builds upon the legacy of the late Hubert J.P. Schoemaker, Ph.D., a visionary pioneer in biotechnology and a native of the Netherlands, who was the co-founder of Centocor, now Janssen Biologics. Centocor engaged in an auspicious collaboration with Wistar to advance the Institute’s seminal research in monoclonal antibodies into a commercial platform. More importantly, Schoemaker believed in mentoring the next generation of innovative scientific leaders, which is the inspiration behind this program.

Together with Wistar’s work with Batavia Biosciences, the Wistar-Schoemaker Postdoctoral Fellowship is set to reprise the historical collaboration between Wistar and the Dutch biomedical research arena, expanding Wistar’s international partnerships in research and education and promoting scientific exchange between investigators in the Netherlands and the United States.

“Building more opportunities for international exchange in the training of junior scientists benefits all those involved,” said Dr. Dario Altieri, Wistar president and CEO. “International mobility offers invaluable opportunities for personal and professional development for students and trainees. At the same time, they enrich the host institution with their scientific and cultural background and, when they return to their home countries, they propagate the knowledge they’ve acquired and the scientific approach they have been exposed to. Last but not least, exchange programs create new opportunities for research collaboration.”

Due to the COVID-19 pandemic, a hold was placed on international travel and students were unable to begin their training at Wistar in 2020. However, designed with training in mind, the program also created a connection to establish new scientific collaborations between the two institutions that share several areas of research interest. Eager to begin the partnership, Wistar and LUMC came together for virtual seminars between the scientific leaders and faculty from both institutions to highlight potential collaborative avenues.

It is exciting to think of all of the potential scientific, cultural and commercial collaborations that are possible between the Philadelphia region and the Netherlands. Wistar is proud to play a small role in this developing relationship and looks forward to more partnerships in the future.

In June, 2021, Wistar leadership met with the Consul General of the Kingdom of the Netherlands, Mr. Herman Quarles van Ufford and team to discuss our joint missions, exciting scientific collaborations and contributions to the life science community, including the Schoemaker International Fellows Program with Leiden University Medical Center, to our work on rubella with Batavia, to our interest in advancing multi-investigator research collaborations and corporate partnerships. There is a great deal to be excited about — and so much more that we can do that would benefit both the Philadelphia region and the Netherlands.

Research Collaborations in the Montaner Lab, Progress Toward an HIV Cure

Written by The Wistar Institute on October 1, 2021. Posted in Featured News.

Dr. Luis Montaner is a transformative leader in HIV research. Throughout his tenure at Wistar, his discoveries to find an HIV cure have elevated both the prestige and scientific prowess of the Institute while most importantly, helped inform the treatments for people around the globe suffering from HIV.

Montaner has spent the last 26 years at The Wistar Institute researching HIV infection and how to boost the immune system to fight the disease. With the goal of advancing treatment strategies toward HIV eradication, his research combines virology and immunology to study the mechanisms of HIV virus infection. Montaner is also involved in overseeing patient enrollment into innovative clinical trials through advocacy partners such as Philadelphia FIGHT, and this summer, he and his partners were awarded a $29.15 million Martin Delaney Collaboratories for HIV Cure Research award to the BEAT-HIV Martin Delaney Collaboratory to advance combination immunotherapy research towards a cure for HIV. This funding extends a grant originally awarded in 2016 based on research progress to date.

Dr. Luis Montaner joined Wistar in 1995 as an assistant professor and was promoted to professor in 2007. He holds many positions at Wistar including vice president, Scientific Operations; Hebert Kean, M.D., Family Professor; associate director for Shared Resources, The Wistar Institute Cancer Center; and director, HIV-1 Immunopathogenesis Laboratory and leader, HIV Research Program. Since his arrival, Luis has been a proponent of the power of scientific collaboration. He believes that by joining intellectual and resource strengths with partners, he can advance research faster and achieve better outcomes. As illustrated in the map, the Montaner lab collaborative studies extend from Philadelphia across the United States and Puerto Rico to Mexico, Europe, South America, Southern Africa, and Asia.

His work relies on laboratory models of viral infection, such as animal models, together with clinical cohort studies, to provide a clinic-to-bench research program. This approach informs new strategies to combat HIV that may also change how we think about prevention and treatment of other infectious diseases and cancer.

“Research moves faster and with greater impact when you bring together several experts with different knowledge and areas of discovery,” said Dr. Montaner. “Just like an orchestra conductor can draw different sounds to support the execution of a symphony, the ability to draw from basic researchers, animal model experts, clinicians, industry experts, international advisors, and community members under a common shared effort helps us accelerate progress towards an HIV cure.”

Nothing exemplifies the power of collaboration more than the incredible progress the HIV research field has enabled over the last forty years in diagnosing, treating, and preventing HIV. Even recently, from 2010 to 2017, the rate of HIV-related deaths among people 13 years and older in the United States fell by nearly half according to a study from the Center for Disease Control and Prevention.

Much has been accomplished in the HIV research field, however there is still so much more to do, including the continued pursuit of a successful HIV vaccine and ultimately a cure for HIV. In this pursuit for a cure, Dr. Montaner currently leads one of the largest coalitions of NIH-funded, HIV cure-directed research under the BEAT-HIV Delaney Collaboratory. This enormous consortium brings together more than 70 top HIV researchers from academic research institutions around the world working with government, nonprofit organizations, and industry partners to test combinations of several novel immunotherapies under new preclinical research and clinical trials. The common goal of the Collaboratory is to achieve an accessible and safe strategy that can either sustain control of HIV without the continued use of current therapies and/or eradicate HIV.

While global collaborations are important, Luis has always been a huge proponent of the power of local collaborations. Within Philadelphia, his lab has a long-standing partnership with Philadelphia FIGHT, a comprehensive health services organization providing primary care, consumer education, research and advocacy for people living with HIV/AIDS and those at high risk. Representing an academic-community partnership that is unique in HIV research, Philadelphia FIGHT and the University of Pennsylvania along with the Robert I. Jacobs Fund of The Philadelphia Foundation, developed the HIV-1 Patient Partnership Program to provide clinical material for basic research and to sponsor the Jonathan Lax Memorial Lecture. Research with clinical material obtained from this Program is focused on mechanisms of AIDS immunopathology. This collaborative link between Montaner’s research team and more than 5,000 people living with HIV/AIDS in the Philadelphia region has led to the largest HIV Cure clinical trial to date — the BEAT-HIV Study. Their partnership with Philadelphia FIGHT strives to develop trusted relationships and maintain meaningful, bi-directional lines of communication between scientists and communities most affected by HIV. HIV Social Science has been a recent addition to the Montaner lab program to enhance both their preclinical and community engagement efforts.

Opportunity for progress is unique and unparalleled at present but so is Wistar’s collective responsibility to deliver.

Learning How to Read the Book of Life

Written by The Wistar Institute on September 30, 2021. Posted in Featured News.

Research in the Gene Expression & Regulation Program at Wistar continues to reveal new knowledge on RNA and its functions to regulate how our genes are expressed and how that can go awry.

The advent of mRNA vaccines for COVID-19 — touted as the next-generation tool in vaccinology — brought RNA to the fore, giving popularity to this once less-publicized cousin of DNA.

In high school biology, we learned that our genes are the repositories of the blueprint to make all of our proteins. Our genes carry out most of the functions in our cells. RNA is the carrier of information from DNA to ribosomes — the machines that manufacture proteins.

The process of reading and executing the instruction book of life involves strict oversight and multiple levels of regulation to allow a relatively small number of genes to orchestrate all the functions of our body. Control of gene expression plays a critical role in determining what proteins are present in a cell and in what amounts at any given time.

It is becoming abundantly clear that this control process happens both during and after RNA transcription.

Wistar scientists have pioneered the study of RNA biology, discovering new RNA types and unraveling some of the mechanisms that modify RNA to regulate its functions for gene expression. Following along that path, labs in the Gene Expression and Regulation Program continue to delve deep into the RNA world and make exciting discoveries related to RNA structure and functions.

R-LOOPS: Friend-Foes

Dr. Kavitha Sarma, assistant professor, focuses on particular nucleic acid structures called R-loops that contain both DNA and RNA and form during transcription, the first step of gene expression.

In our DNA book, consider genes as the individual words and nucleotides as the letters that make up those words. When a DNA template is “transcribed” into messenger RNA (mRNA), the sequence of letters that form each gene gets “read” and copied into an RNA molecule that will leave the nucleus and travel to the cytoplasm, where words will be read by ribosomes to provide instructions for making proteins.

Sometimes during transcription, the newly synthesized RNA molecule sticks to its template DNA strand, forming a stable DNA/RNA hybrid that appears like a loop when visualized by electron microscopy, hence the name R-loop.

This is a normal occurrence — R-loops are constantly formed and removed throughout the genome and their presence can be beneficial for transcriptional regulation. However, accumulation of R-loops can cause DNA damage, chromosome rearrangements and genomic instability and underlie a host of diseases from cancer to neurodegenerative disorders and possibly autism.

The Sarma lab is interested in R-loops for their potential in causing disease and in serving as new therapeutic targets. They have been busy developing new, improved techniques to detect R-loops to study the contributions of these structures in gene regulation and the consequences of their accumulation in the cell1.

Thanks to these technological advances, Dr. Sarma and her colleagues were able to identify new factors that regulate R-loops and are now closing in on their function in glioblastoma and colon cancer.

The lab received funding from the W.W. Smith Charitable Trust to study the role of R-loops in brain cancer and with support from the Basser Center for BRCA and the Margaret Q. Landenberger Research Foundation they are dissecting the correlation between R-loop formation and BRCA1/2 gene mutations in breast and ovarian cancer to eventually use R-loops for novel diagnostic and therapeutic applications. The Simons Foundation supports the lab’s work elucidating the consequences of unregulated R-loops in autism spectrum disorders.

EDITING RNA TO RESOLVE R-LOOPS

Dr. Kazuko Nishikura, professor, has published a new function of R-loops2 in preserving the integrity of our chromosome ends — the telomeres.

Dr. Nishikura has been a pillar of Wistar science for almost four decades with a career overlapping with the rise and expansion of the RNA biology field. She was one of the first to characterize a process called RNA editing and its multiple functions in the cell, and to discover the enzyme ADAR1 that is responsible for it.

RNA editing changes one or more letters in RNA “words,” allowing cells to make discrete modifications to an RNA molecule. RNA editing is a good example of how our cells make the most of their genes and create different protein products from a single gene by slightly modifying the RNA sequence.

With support from grants from the National Institutes of Health and Emerson Collective, the Nishikura lab recently showed that ADAR1 helps the cells resolve R-loops formed at the chromosome ends and prevents their accumulation by facilitating degradation of the RNA strand.

Nishikura and colleagues found that depletion of a particular form of the ADAR1 protein leads to extensive telomeric DNA damage and arrested proliferation specifically in cancer cells, indicating this process as a new target for cancer therapy.

ALTERNATIVE POLYADENYLATION: Tell Me What Your APA Is and I Will Tell You Where to Go

An important level of mRNA regulation involves modifying its structure, especially at the tail end of the sequence, termed 3’ end. A process called polyadenylation adds a stretch of specific nucleotides to protein-coding mRNAs to regulate their stability, transportation from nucleus to cytoplasm and translation into proteins.

Dr. Bin Tian, professor, and his lab study this process to understand regulatory mechanisms and to identify new drug targets. They have contributed important knowledge on polyadenylation in normal and diseased conditions, including the discovery that alternative polyadenylation (APA) is widespread across genes.

This is a dynamic mechanism of gene regulation that generates different 3′ ends in mRNA molecules, resulting in multiple mRNAs from the same gene, which scientists call isoforms.

The lab’s latest research is uncovering the role APA plays in facilitating protein production in certain sites within the cell where those proteins are most needed.

When mRNAs leave the nucleus and move to the cytoplasm, they need to be properly directed to reach the ribosomes and be translated into proteins. Although too small to be seen with the naked eye, a cell is a huge space for something as tiny as an mRNA molecule that has to find its way. Imagine finding yourself in a baseball stadium and not knowing how to get to your seat.

The Tian lab discovered that some mRNAs possess specific properties in their sequence and structure that enable them to associate with the endoplasmic reticulum (ER), a network of tubes that build, package and transport proteins and where a large fraction of ribosomes in the cell are located3.

These mRNAs tend to encode for proteins involved in cell signaling, the process that allows the cells to communicate with neighboring cells by sending, receiving and processing signals to respond to changes in their environment.

Dr. Tian and his team hypothesize that association with the ER anchors certain mRNA isoforms in specific cellular locations where important signaling events happen, making the whole process more efficient. According to this model, the ER would serve a new function as a scaffold to keep proteins at hand where they are needed, representing a platform that provides venues for signaling events to happen quickly and effectively.

The lab also creates computer-based data mining tools to analyze APA using large data sets, such as those from The Cancer Genome Atlas (TCGA) program.

The extraordinary biological complexity of human life is a reflection of the many sophisticated ways in which gene expression can be fine-tuned.

The cutting-edge science underway at Wistar pushes the limits of RNA research to advance our understanding of how the human genome is decoded, how the messengers of genetic information are guided, and how accidental mistakes that happen while reading and interpreting the DNA book can be fixed, all of which may enable researchers to develop novel and more precise ways to treat diseases.

1 A nuclease- and bisulfite-based strategy captures strand-specific R-loops genome-wide, Elife 2021
2 ADAR1 RNA editing enzyme regulates R-loop formation and genome stability at telomeres in cancer cells, Nature Communications 2021
3 Alternative 3’UTRs play a widespread role in translation-independent mRNA association with endoplasmic reticulum, Cell Reports 2021

Combining Expertise, The Wistar Institute and Batavia Biosciences Partner to Expand Rubella Vaccine Manufacturing Around the World

Written by The Wistar Institute on September 29, 2021. Posted in Featured News.

Companies that make rubella vaccines have been getting harder and harder to come by. The global production of the rubella vaccine, supplied in combination with measles, mumps and varicella vaccines, which is the typical route for rubella immunization, is limited to a small number of manufacturers, which could threaten the ongoing global supply of these critical medicines.

This situation is exactly what The Wistar Institute wants to avoid. In the 1960s at Wistar, Stanley A. Plotkin, M.D., now a professor emeritus, developed the rubella vaccine that put an end in much of the world to the epidemics that caused infants to be born deaf and have other defects. Dr. Plotkin’s vaccine strain is used today in most of the 173 countries that include rubella in their national immunization programs. “As the originator of the rubella vaccine, Wistar has a mission to protect its longevity,” said Heather Steinman, Ph.D., MBA, Wistar’s vice president for business development.

To that end, Wistar has made strides over the years licensing the rubella vaccine to companies in developing countries. But that approach has downsides. It can take companies many years to bring the vaccine, which Wistar supplies as research-grade seed stock called RA 27/3, through the many stages of testing, manufacturing and clinical development that are required before the rubella vaccine can be administered to people. It is a substantial investment of resources for vaccine manufacturers, and at the end of it, there is little to no profit for the vaccine manufactures, noted Heather.

A new partnership that Wistar announced in April 2020 with Batavia Biosciences, based in the Netherlands, is poised to overcome these hurdles and quickly expand access of this critical vaccine in developing countries. Together the non-profit and industry pair can deliver new vaccine manufacturers all the resources to get up and running. Wistar will provide its vaccine seed stock while Batavia will rely on its extensive vaccine production expertise to support technology transfer and assist vaccine manufacturers throughout the preclinical and clinical development processes. “Public-private partnerships are critical to fixing global problems, it just made sense for Batavia and Wistar to work together,” Heather said.

This international academic-industry collaboration would not be possible without funding from a non-profit partner, the Bill & Melinda Gates Foundation. Wistar received a $1M grant at the end of 2019 to allow the institute to archive its RA 27/3 seed stock and transfer the necessary supplies to Batavia. “The generous support from the Gates Foundation, which like us has a mission to address some of the world’s most pressing global health challenges, has had a tremendous impact on our partnership with Batavia and has allowed us to advance the work on rubella vaccines beyond Wistar,” said Anita Pepper, Ph.D., Wistar’s vice president for institutional advancement.

Packaging Expertise

The Wistar-Batavia partnership means that vaccine manufacturers that license the rubella vaccine from Wistar will receive a “complete starter kit” of information to speed their entry into the market, said Christopher Yallop, Ph.D., chief operations and scientific officer of Batavia Biosciences. The package, which should be ready by the first half of 2022, will include the production methods that Batavia developed, as well as the virus stock and cells that the company can grow in their facility to propagate more virus. And because Batavia will provide the virus produced using GMP (good manufacturing practice), companies can use it to start clinical trials immediately, as they will have to do to validate the vaccine’s effectiveness and safety in their region.

On top of the one-stop-shop nature of the package, vaccine manufacturers may choose to further benefit by receiving methods that Batavia developed to make rubella vaccine production more efficient. By using new approaches to manufacture the vaccine and new types of equipment, Batavia managed to intensify the process to propagate virus by about 20-fold, which in turn reduces the number of people involved, the overhead and materials costs, reducing the overall cost of the vaccine.

“Many of the vaccines that have been around since the 60s and 70s are made with technologies that were developed in the 60s and 70s so they are not really up-to-date,” Chris said. By increasing production efficiency, “companies can sell the vaccine at a price that the world can pay while being sustainable for them.” Batavia has been involved in collaborations with other academic partners, which were supported by the Gates Foundation, to improve efficiency of production of many global health vaccines including polio, measles & rubella and rotavirus vaccines.

Rolling Out

Now that the Wistar-Batavia collaboration has hit its major milestones, it is ready to set up licensing agreements with interested vaccine manufactures and ship out the package. Both partners expect this step to be an easy one, with the extensive networks of vaccine manufacturers they each have in developing countries. Wistar is already working with vaccine manufacturers in underrepresented countries, Heather noted. India is one of a growing number of countries to add the rubella vaccine to its childhood immunization program, which it did in 2017.

As companies work to join the rubella vaccine market, they will invariably encounter technical issues and require support. Batavia will be the main go-to for addressing these issues, although Wistar will also be involved if they can offer guidance based on their decades of experience growing and studying the rubella vaccine strain, Chris noted.

Speaking to the unique strengths of the academic-industry partnership, Chris highlighted the extensive and complementary skill sets of Wistar and Batavia. No academic research center, whether a small private institute such as Wistar or a large university, can invest the time to develop the vaccine production conditions as Batavia and other life sciences can. On the other hand, Batavia does not have Wistar’s long history of discovery and study of the vaccine. The two are already discussing how they can apply the model for rubella vaccine production to other vaccines and medicines.

“From discovery of the vaccine to licensing, it is almost like Wistar is the beginning and the end of the rubella vaccine chain,” said Anita.

Written by, Carina Storrs, Ph.D.

Wistar and Penn Medicine Awarded $11.7 Million Melanoma Research Grant from the National Cancer Institute

Written by The Wistar Institute on September 22, 2021. Posted in Press Releases.

PHILADELPHIA — (Sept. 22, 2021) —The Wistar Institute and Penn Medicine have been awarded a prestigious $11.7 million Specialized Programs of Research Excellence, or SPORE, grant from the National Cancer Institute. The five-year award will fund three new melanoma research projects that translate fundamental laboratory discoveries made at The Wistar Institute and in the Perelman School of Medicine at the University of Pennsylvania into new therapeutics to treat skins cancers.

The grant also includes a career enhancement program focused on training and retaining underrepresented minorities in skin cancer research, and a pilot award program that will expand research into non-melanoma skin cancer.

The SPORE team at Wistar and Penn will carry on a long tradition of developing new treatments for skin cancer with the grant, which follows a $12 million SPORE grant awarded to the institutions in 2014. The new projects will be supported by core research labs, including a tissue specimen core with over 11,000 banked specimens.

Meenhard Herlyn, D.V.M., D.Sc., director of Wistar’s Melanoma Research Center and professor in the Molecular & Cellular Oncogenesis Program in Wistar’s Cancer Center, and Ravi K. Amaravadi, M.D., associate professor of Hematology-Oncology in Penn’s Perelman School of Medicine and the co-leader of the Cancer Therapeutics Program at Penn’s Abramson Cancer Center, and will serve as the co-directors of the SPORE.

“Despite dramatic improvement brought about by immunotherapy, we still have major challenges for the majority of patients and new approaches are urgently needed,” said Herlyn. “Building on major breakthroughs by our team, we are poised to address crucial unanswered questions to improve immunotherapy response and identify new biomarkers to inform patient management and reduce therapy toxicity.”

“Our longstanding team approach to science and new therapies has been recognized by the NCI once again with this new SPORE grant. We can now expand on this collaboration—which has already led to important developments in melanoma,” Amaravadi said. “From new fundamental insights about how skin cancer escapes treatments to new treatment options for patients, these projects—and the people leading them—are at the cutting edge of translational medicine, and are entirely focused on improving the health of our patients.”

Melanoma is the deadliest form of skin cancer and the fifth deadliest form of cancer, overall. According to NCI statistics, more than 100,000 new cases of melanoma will occur in 2021 in the U.S. alone. The incidence of melanoma and other skin cancers, such as Merkel cell carcinoma and squamous cell carcinoma, are rising both nationally and regionally. If caught early, skin cancer is considered treatable; however, when these cancers metastasize, they are especially deadly.

Other Wistar faculty on the team include professor David W. Speicher, Ph.D., associate professor Jessie Villanueva, Ph.D., and assistant professor Andrew Kossenkov, Ph.D., from The Wistar Institute Cancer Center.

Other Penn faculty involved with the project include Wei Guo, PhD, the Class of 1965 Endowed Term Chair in Biology, Xiaowei Xu, MD, PhD, a professor of Pathology and Dermatology, Phyllis Gimotty, PhD, a professor of Biostatistics and Epidemiology, Giorgos Karakousis, MD, an associate professor of Surgery, Gregory Beatty, MD, PhD, an associate professor of Medicine, Tara Mitchell, MD, an associate professor of Medicine, Lynn Schuchter, MD, chief of Hematology-Oncology and director of the Tara Miller Melanoma Center, and E. John Wherry, Chair of the department of Systems Pharmacology and Translational Therapeutics.

The three main SPORE melanoma research projects include:

Project 1: Exosomal PD-L1 in immunotherapy resistance

Co-Project Leaders: Guo, Xu, Mitchell, and Wherry

Currently, there is no approved assay that can help determine which melanoma patients will respond to immunotherapy. This project builds on a fundamental discovery that small segments of cells called exosomes that carry PD-L1 on their surface are floating in the blood of melanoma patients. Exosomal PD-L1 is an immunosuppressive factor, and can be measured in the blood noninvasively with assay developed by Guo and Xu. Working with collaborators at the John Wayne Cancer Institute, MD Anderson Cancer Center and New York University, the team will conduct rigorous clinical utility studies designed to demonstrate this blood-based measurement as a highly sensitive and specific predictive biomarker for response to immunotherapy in melanoma.

Project 2: Targeting autophagy to improve immunotherapy in melanoma

Co-Project Leaders: Amaravadi and Speicher

Currently, there are limited options for patients whose tumors have progressed on immunotherapy in melanoma. Based on extensive preclinical data and a new molecular target in the autophagy pathway, the team has developed a clinical trial of combined immunotherapy and autophagy inhibition. Targeting autophagy during immunotherapy can reprogram cells within the tumor to enhance the efficacy of T cell killing of melanoma cells. This clinical trial will include a novel PET imaging tracer that can track T cells as they enter the tumors in patients. The project also works with several biotech companies developing new autophagy inhibitors for cancer.

Project 3: Neoadjuvant immunotherapy for early-stage melanoma

Co-Project Leaders: Beatty, Karakousis, and Herlyn

Currently, patients with stage III melanoma are treated with immunotherapy after surgical resection. Some stage II melanoma patients have a higher risk of metastasis than stage III patients, but there is no approved therapy to reduce this risk. Based on previous work showing that one cycle of immunotherapy given before surgery can produce major benefits in stage III melanoma patients, the team has launched a clinical trial of neoadjuvant immunotherapy in stage IIB/C melanoma patients. Besides in-depth characterization of the immune response, the project’s preclinical studies, which include several innovative mouse models to study immunotherapy in stage II melanoma, will lead to new strategies for enhancing the immune stimulatory capacity of dendritic cells in the tumor microenvironment.

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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.

Wistar Scientists Identify New Therapeutic Target in Ovarian Cancer Subtype With Poor Prognosis

Written by The Wistar Institute on September 21, 2021. Posted in Press Releases.

PHILADELPHIA — (Sept. 21, 2021) — Mutations in the ARID1A gene are present in more than 50% of ovarian clear cell carcinomas (OCCC), for which effective treatments are lacking. Scientists at The Wistar Institute discovered that loss of ARID1A function enhances a cellular stress response pathway that promotes survival of cancer cells, which become sensitive to pharmacological inhibition of this pathway. These findings were published online in Cancer Research, a journal of the American Association for Cancer Research, and point to a new therapeutic opportunity for this type of ovarian cancer for which new solutions are urgently needed.

Inactivating mutations in the ARID1A tumor suppressor gene are genetic drivers of OCCC, which does not respond to chemotherapy and carries the worst prognosis among all subtypes of ovarian cancer.

“The goal of our research is to uncover the molecular changes caused by ARID1A loss so that we can target them specifically to achieve effective therapies for this devastating disease,” said Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center, professor and leader of the Immunology, Microenvironment & Metastasis Program, and lead author of the study. “In this study, we focused on a stress response mechanism that tumors resort to for survival and found a link that offers a therapeutic opportunity.”

The endoplasmic reticulum (ER) is a cellular structure that oversees protein production and harbors complex mechanisms to respond to the stress caused by accumulation of misfolded proteins. The ER stress response is frequently hyperactivated in cancer cells to favor their survival in stressful microenvironment conditions. Therefore, inhibition of this mechanism has been explored as a therapeutic approach for cancers with hyperactive ER stress response.

The IRE1a/XBP1 pathway is the major signaling pathway involved in the ER stress response. The protein Inositol-required enzyme alpha (IRE1a) senses ER stress and activates the transcription factor X-box binding protein 1 (XBP1), resulting in upregulation of genes that resolve the ER stress and promote cell survival.

Zhang and colleagues found that ARID1A inhibits the IRE1a/XBP1 pathway and, consequently, ARID1A loss in ovarian cancer causes an increased activation of the pathway, creating a dependence of cancer cells on upregulated IRE1a-XBP1. Indeed, treatment of ovarian cancer cells that do not express ARID1A with the selective IRE1a inhibitor B-I09 caused cell death as a result of unresolved ER stress.

“In some cases, the mechanisms cancer cells exploit to their advantage also make them vulnerable because they become dependent on certain pathways,” added Zhang. “If we can find ways to block those pathways, we may be able to use them as weak spots for killing cancer.”

Importantly, this observation was confirmed in vivo, as B-I09 treatment reduced tumor burden and improved survival in mouse models bearing ARID1A-inactivated ovarian tumors.

Therapeutic resistance enables cancer cells to escape the effects of single agent treatments, and combination strategies offer a solution for this major challenge. Therefore, researchers tested the combination of IRE1a inhibition with histone deacetylase 6 (HDAC6) inhibition, which is also effective against ARID1A-mutant cancers. Since HDAC6 regulates the degradation of misfolded proteins, the team hypothesized that the two treatments may act in synergy to suppress ARID1A-mutant cancers.

“Our findings suggest that pharmacological inhibition of the IRE1a/XBP1 pathway of the ER stress response, alone or in combination with HDAC6 inhibition, represents a potential therapeutic strategy for ARID1A-mutated cancers,” said Joseph Zundell, a pre-doctoral trainee in the Zhang lab and first author on the paper.

Co-authors: Takeshi Fukumoto, Jianhuang Lin, Nail Fatkhudinov, Timothy Nacarelli, Andrew V. Kossenkov, Qin Liu, Joel Cassel, and Shuai Wu from The Wistar Institute; Chih-Chi Andrew Hu from Houston Methodist Research Institute.

Work supported by: National Institutes of Health (NIH) grants R01CA202919, R01CA239128, R01CA260661, P50CA228991, R01CA163910, R01CA190860, and F31CA247336; US Department of Defense grants OC180109 and OC190181; The Honorable Tina Brozman Foundation for Ovarian Cancer Research and The Tina Brozman Ovarian Cancer Research Consortium 2.0; and Ovarian Cancer Research Alliance [Collaborative Research Development Grant #596552 and Ann and Sol Schreiber Mentored Investigator Award #649658]. Core support for The Wistar Institute was provided by Cancer Centre Support Grant P30CA010815.

Publication information: Targeting the IRE1a/XBP1 endoplasmic reticulum stress response pathway in ARID1Amutant ovarian cancers, Cancer Research, 2021. Online publication.

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Dr. Noam Auslander: New Faculty Addition Brings Artificial Intelligence Research to Wistar

Written by The Wistar Institute on September 15, 2021. Posted in Featured News.

Wistar welcomes Dr. Noam Auslander as an assistant professor in the Cancer Center’s Molecular & Cellular Oncogenesis Program. She applies artificial intelligence (AI) through high-throughput computer approaches to interpret the very large sets of data biomedical research produces.

Q: What’s the role of artificial intelligence in biology?

A: Using AI, we can process big and complex datasets, integrate different data types, extract new knowledge, and identify patterns that describe specific features or outcomes that we are interested in. Using computing power, we try to identify complex patterns in the data to uncover biologically and clinically relevant information and help predict prognosis and treatment response. While AI has deeply transformed other fields, we are not exploiting its full potential in biology yet, but we’re getting there. For example, deep learning methods are currently outperforming any other approach to predicting protein structure.

Q: What attracted you to AI and machine learning?

A: I double majored in computer science and biology because I liked both disciplines. During my Ph.D. training in computer science, I specialized in computational biology and I realized that almost any biologic question could be tackled through AI and that computing power can help analyze very complex data sets.

Q: What are your research interests and goals?

A: I’m interested in how cancer evolves during disease progression. Over time, cancer cells accumulate mutations and other features that favor
their continued growth and survival and eventually promote metastasis. Cells carrying the most favorable alterations are selected, leading to the emergence of different populations. Deciphering this process has important implications for therapy response and resistance to treatment. I also study the evolution of viral infections. I approach these topics using artificial intelligence and develop new software and algorithms to answer different biologic questions.

Q: How will your research and expertise fit into Wistar’s research programs?

A: My research is very collaborative by nature: My lab won’t generate primary data from lab experiments. Instead, we will apply our computational expertise working with other teams to enhance the potential of their data. I see many promising opportunities for collaboration, for example with the Herlyn lab on immunotherapy in melanoma and the Zhang lab on ovarian cancer. I’m excited to join such a dynamic and collaborative environment.

Q: How will your work with scientists support what they do?

A: I think that AI can be useful for many ongoing research projects at Wistar. It can be used, for instance, to identify biomarkers, develop clinical predictors, and uncover deleterious alterations. We can utilize these tools to identify candidate genes or mutations that confer treatment sensitivity or resistance and to predict genomic features that enhance viral pathogenicity and infectivity. Therefore, with the expansive growth of genomic, molecular, and clinical data, machine and deep learning methods offer unique opportunities for biomedical research.

Q: Tell us a little about where you came from, your background, and your interests.

A: I grew up in Israel, where military service is mandatory for everyone, so it’s really nothing special. I served in the Intelligence Corps of the IDF between 2008-2010. My unit was in the School of Intelligence, and we worked on computer-based training projects, where I was team leader of computer graphics from 2009.

I absolutely love research. It’s so much fun that I consider my work also a hobby. I also enjoy sports: long distance running, skiing and snowboarding. Growing up in Israel you’re not exactly close to the mountains, but I used to go skiing in the Alps and loved it. I’ve found many great places in the U.S. too.

Dr. Hildegund Ertl: Vaccine Thought Leader and Formidable Presence

Written by The Wistar Institute on September 15, 2021. Posted in Featured News.

Dr. Hildegund Ertl, Wistar immunologist and vaccine developer, has been featured in local and national media and sought after by journalists as a source of expert opinions. A well-spoken scientist, always available to help unravel the many questions related to the varied COVID-19 vaccines, she is also working on her own vaccine.

“I enjoy talking to reporters, some ask very interesting and thought-provoking questions,” said Dr. Ertl, who is a professor in the Vaccine & Immunotherapy Center and was the founding director of the former Wistar Vaccine Center. “The main reason why I feel compelled to answer those questions is to lend my voice against vaccine hesitancy, a threat to public health and especially serious during a pandemic. I think I have something to offer to this cause because I’ve studied vaccines all my life and I hope that experts going on TV or in papers saying that vaccines are safe will convince more people to get vaccinated. These vaccines are our best bet to end the emergency, they are safe and are being monitored extremely carefully.”

Dr. Ertl and her team are researching and developing vaccines for many infectious diseases, including HIV and cancer. And for the last two decades, Dr. Ertl has been studying adenoviruses, one of the common cold viruses, as a carrier for vaccine delivery.

Since adenovirus infections are common in people, most would be immune to them and a vaccine created from a human adenovirus might not be potent enough to prevent infection. To circumvent this issue, Dr. Ertl’s team uses chimpanzee adenoviruses, against which humans do not have immunity.

Dr. Ertl has worked on immunology and vaccine research since the very beginning of her career and as part of her medical training.

“During my internship and residency in microbiology, I enjoyed interacting with patients. I was very young looking and my very first patient, to whom I was supposed to administer a vaccine, looked at my baby face and said he would not let me touch him, and left,” she recalls. “That convinced me that I was better off pursuing my main passion: research and biology.”

After a two-year prestigious research fellowship in Australia, Dr. Ertl was recruited by Harvard and eventually joined Wistar in 1987 and has been a steady and productive member of the faculty ever since. “I never left because I care deeply about Wistar,” she said.

In these three decades, Dr. Ertl witnessed the many changes the Institute — and academia in general — went through.

“I think with funding restrictions came a tendency for scientists to turn away from basic research and go with the flow of what is ‘hot’ at the moment, while innovative ideas are less supported,” Dr. Ertl noted. “I think this is going to have a cost in the long run.”

“Other aspects have greatly improved, though. Women, for example, have it easier now than when I started. Science used to be much more discriminatory against women. I would propose an idea and my colleagues would not care for it, except everyone would love that same idea at a later time when it came from a man.”

“Personally, I don’t think this affected me in major ways,” Dr. Ertl added.

“Besides being very determined, I’m tall and naturally a bit abrasive, so I think I can be intimidating and that helped me stand up for myself,” she said.

The direct and candid attitude with which she gets her point across has also served her well in her scientific and academic career.

If she could do her career all over again, Dr. Ertl wouldn’t change much. “During lockdown I realized I should have taken more vacations and traveled more. I love places like Amazonia, Mongolia and Alaska, with few people and a lot of nature.”

For now, you can find her in the lab every day.

“I don’t like working from home. There’s a place for everything — home is where I am my private self, while the lab is where I’m Dr. Ertl. I enjoy both aspects of my life, but I think there needs to be a separation.”

“When I’m home, I like gardening. I have a big yard because I have a house full of pets: two Great Danes, three cats and a parrot I call Matilda,” she said. “You can say it’s a mad house, but chaos doesn’t bother me. At some point I’ve had up to eight graduate students in my lab, and that can be quite chaotic too.”

“I also love reading and hunting for good second-hand books at the library, which of course the pandemic has ruined.”

When asked if she ever misses Europe, where she grew up, Dr. Ertl said that she might move back there or to North Africa, where her family lives, after her retirement.

“But obviously I’m not going to retire anytime soon.”

Dr. Ertl is one of our key opinion leaders at Wistar, and you can read more about her scientific views in her latest articles by going to: wistar.org/news.