Author: The Wistar Institute

Dr. Dario Altieri smiles in a Wistar lab

Wistar Scientists Identify Therapeutic Target for Metastatic Cancers

Written by The Wistar Institute on February 17, 2022. Posted in Featured News.

Damaged “ghost” mitochondria are found to drive tumor progression.

Metastasis, or the spread of cancer from one place in the body to another, is responsible for more than 90% of all cancer deaths. Therefore, determining how and why this happens is an important part of cancer research. A new collaborative study led by scientists at The Wistar Institute identified one such mechanism thanks to “ghost” mitochondria.

Because they are the “powerhouse” of the cell, mitochondria (a specific organelle inside human cells) are crucial for cell survival, including tumor cells. However, recent research has shown that mitochondria in many human tumors lack an important protein called Mic60. Normally missing a crucial protein is a recipe for disaster, yet these mitochondria and their cells survive.

To determine how this is possible and how it affects tumor cell behavior, Dario C. Altieri, M.D., Wistar president and CEO, director of The Wistar Institute Cancer Center, and the Robert & Penny Fox Distinguished Professor, led a team of researchers in reproducing these types of low-Mic60 tumor cells in mice to enable closer examination. In doing so, they found two things. First, in cells where Mic60 was depleted, all of the mitochondria’s structures and functions were damaged or inhibited.

“They really didn’t produce any energy, which is what mitochondria do,” said Altieri. “That was the idea of calling them ‘ghosts’—because in essence the mitochondria were still there, but they didn’t do anything, or anything good, at least.”

Second, the scientists found that while inferior organelles are usually removed from healthy cells via a quality control process, the ghost mitochondria were not removed from tumor cells. Not only were they not removed, but they helped the cell metastasize.

Given these findings, the scientists speculate that the low-Mic60 tumor cells activate two pathways to stay alive: Akt (related to survival) and GCN2 (related to stress response). Drugs interfering with these pathways could, therefore, help to stop metastasis and kill the cancer.

“The idea would be to eliminate the adaptive responses that these Mic60-low tumors mount to remain alive and viable through a combination targeting of Akt and GCN2,” said Altieri.

Dr. Daniel Kulp works with a fellow scientist in a Wistar lab

Wistar Study Opens the Door to Faster, Cheaper HIV Vaccine Research

Written by The Wistar Institute on February 4, 2022. Posted in Featured News.

For the first time, scientists have developed an DNA-encoded immunogen that produces Tier-2 antibodies—the kind that matter for combatting HIV

Nearly four decades after its discovery, HIV has killed 36.3 million people, with no vaccine in sight. Part of the reason vaccine development has been slow is because trialing candidate vaccines that produce Tier-2 neutralizing antibodies—the kind that matter for combatting HIV—has always required long and expensive experiments in large animal models like rabbits and macaque monkeys.

An effective HIV vaccine needs to produce antibodies that protect against the most common variants of HIV, which are categorized as “Tier 2” viruses based on how quickly and easily they can be neutralized by antibodies (more quickly/easily than Tier 3, less than Tier 1).

A new study by scientists at The Wistar Institute shows a quicker, less expensive path to developing this tier of antibodies. For the first time, these scientists have demonstrated a method for eliciting Tier-2 neutralizing antibodies in mice.

“Mice are the workhorse of vaccine design and development because you can iterate lots of concepts in that model due to cost and time constraints,” said Daniel Kulp, Ph.D., associate professor in the Vaccine & Immunotherapy Center at The Wistar Institute.

The scientists developed an immunogen—a substance that causes an immune response—called a native-like trimer, which they administered to mice. Importantly, they encoded the immunogen in DNA, which turns the host bodies (in this case the mice) into “antigen factories” instead of requiring what would otherwise be a complex and expensive vaccine manufacturing process.

They then compared the results from the mice who received the DNA-encoded native-like trimer to results from mice who received a standard protein immunization. Only those mice that received the DNA-encoded native-like trimer developed Tier-2 neutralizing antibodies.

From there, they were able to isolate and examine the atomic structure of one of the antibodies that their immunogen had produced. “The structure gives us incredible insight into how this antibody is able to neutralize the virus,” said Kulp.

“Our data demonstrates the value of this approach as a tool to create surgically tailored immunity against a difficult pathogen’s vulnerable sites, in this case for HIV,” said coauthor David B. Weiner, Ph.D., executive vice president and director of the Vaccine & Immunotherapy Center and the W.W. Smith Charitable Trust Professor in Cancer Research at The Wistar Institute.

Wistar Scientists Move HIV Vaccine Research Forward by Developing an Immunogen that Produces Tier-2 Antibodies—the Kind That Matter for Combatting HIV

Written by The Wistar Institute on February 4, 2022. Posted in Press Releases.

PHILADELPHIA — (Feb. 4, 2022) — Nearly four decades after its discovery, HIV has killed 36.3 million people, with no vaccine in sight. However, a new study by researchers at The Wistar Institute, an international biomedical research leader in cancer, immunology, infectious disease, and vaccine development, takes a promising step in the direction of developing an HIV vaccine.

The findings, published in Nature Communications, demonstrate the promise of using a unique native-like trimer to develop Tier-2 neutralizing antibodies—the kind that matter for combatting HIV—in mice for the first time.

Previously, eliciting these types of antibodies using candidate vaccines required long and expensive experiments in large animal models creating a significant bottleneck on HIV-1 vaccine development. “With our new finding, we have opened the door to rapid, iterative vaccinology in a model that can produce Tier-2 neutralizing antibodies, enabling development of more advanced HIV vaccine concepts,” said Daniel Kulp, Ph.D., associate professor in the Vaccine & Immunotherapy Center at The Wistar Institute and corresponding author on the paper.

The researchers encoded the native-like trimer into DNA for delivery into the mice. This has the practical advantage of turning the host bodies into “antigen factories” instead of requiring what would otherwise be a complex vaccine manufacturing process. The researchers then compared the results from the mice who received the DNA-encoded native-like trimer to results from mice who received a standard protein immunization. Only those mice that received the DNA-encoded native-like trimer developed Tier-2 neutralizing antibodies.

“We were able to generate strong immune responses with both platforms, but the DNA platform uniquely drove this neutralizing response,” said Kulp.

Once they’d verified their immunization regime was producing Tier-2 antibodies, Kulp and his colleagues isolated monoclonal antibodies from the mice and used cryo-electron microscopy to determine the atomic structure of one Tier-2 neutralizing monoclonal antibody. They found that the antibody binds to an epitope (a segment of a protein that sticks out of the antigen, which prompts an immune response) called C3V5. In the gold standard HIV vaccine model (non-human primates), prior research has shown that antibodies binding to C3V5 protect animals from a SHIV infection, which is a close relative of HIV that infects non-human primates.

“The structure gives us incredible insight into how this antibody is able to neutralize the virus,” said Kulp. “For the first time, we can strategize about how to design new vaccines that can generate broadly neutralizing antibody responses to the C3V5 epitope.”

Coauthor David B. Weiner, Ph.D., executive vice president and director of the Vaccine & Immunotherapy Center and the W.W. Smith Charitable Trust Professor in Cancer Research at The Wistar Institute, emphasized the utility of their findings.

“What we’ve done is enable direct in vivo self-assembly of structurally designed immunogens, which are engineered and delivered using nucleic acid technology, inside the vaccinated animal. Our data demonstrating induction of autologous Tier 2 neutralization illustrate the value of this approach as a tool to create surgically tailored immunity against a difficult pathogen’s vulnerable sites, in this case for HIV.”

Co-authors: Ziyang Xu, Susanne Walker, Neethu Chokkalingam, Mansi Purwar, Edgar Tello-Ruiz, Yuanhan Wu, Sonali Majumdar, Kylie M. Konrath, Abhijeet Kulkarni, Nicholas J. Tursi, Faraz I. Zaidi, Emma L. Reuschel, Ishaan Patel, April Obeirne, David B. Weiner, and Daniel W. Kulp from The Wistar Institute; Megan C. Wise, Katherine Schultheis, Lauren Gites, Trevor Smith, Janess Mendoza, Kate E. Broderick, and Laurent Humeau from Inovio Pharmaceuticals; Alan Moore, Jianqiu Du, and Jesper Pallesen from Indiana University.

Work supported by: National Health Institutes (NIH) IPCAVD Grant U19 Al109646-04; W. W. Smith Charitable Trust; and Wistar Monica H.M. Shander Memorial Fellowship.

Publication information: Induction of Tier-2 Neutralizing Antibodies in Mice with a DNA-encoded HIV Envelope Native Like Trimer, Nature Communications, 2022. Online publication.

###

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 Behind the Next Wave of COVID-19 Vaccines

Written by The Wistar Institute on February 3, 2022. Posted in Featured News.

Current COVID-19 vaccines were created in record time, but scientists are working to make better, longer lasting vaccines that could be used around the world.

The first generation of COVID-19 vaccines have been highly effective, but also have limitations: their efficacy can wane without a booster shot, and they may be less effective against some variants. Now scientists at The Wistar Institute have developed a more targeted vaccine that, in animal studies, shows stronger, broader, and more durable protection in a single, lower dose.

“This is among the first second-generation vaccines that will have more advanced features and broader protection,” said Daniel Kulp, Ph.D., associate professor in the Vaccine & Immunotherapy Center and corresponding author of the study.

The vaccine combines three technologies — immune focusing, self-assembling nanoparticles, and DNA delivery — into a single platform for the first time.

Immune focusing means that researchers engineered an immunogen that targets specific areas of COVID’s famous “spike” protein to generate protective antibodies. Instead of replicating the whole structure, this immunogen blocks specific sites that produce non-neutralizing antibodies. This stimulates higher production of neutralizing antibodies — the kind of antibodies that help the immune system fight the virus.

Having higher levels of these important antibodies can reduce the chance that the vaccine’s effectiveness will wane over time.

Studies in mice found that 100% of animals who received a single dose of the new vaccine were protected from death after virus challenge, whereas only 20% of animals receiving the first-generation vaccine were protected.

Nanovaccines consist of extremely small (nano) particles—similar in size to bacteria and viruses—used to display multiple copies of an antigen and able to elicit strong immune responses. The new vaccine also uses DNA to instruct cells to make these vaccines. Kulp noted that DNA vaccines can be stored at room temperature, making it potentially easier to transport to remote or developing locations than existing approved vaccines (such as mRNA vaccines), which require specialized cold storage. DNA vaccines historically also have an excellent safety profile, with a very low chance of eliciting severe adverse effects amongst clinical trial participants.

“Current vaccine effects on reducing transmission of SARS-CoV-2 variants of concern including Delta and Omicron could be improved for their breadth of protection as well as their immune potency,” said co-author David B. Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center and the W.W. Smith Charitable Trust Professor in Cancer Research, at The Wistar Institute.

The scientists are seeking funding and partnership to begin human trials of the new vaccine.

Dr. Kulp’s research was made possible through the generous support of Wistar donors who contributed to this project through the Wistar Coronavirus Discovery Fund.

Novel Nanoparticle SARS-CoV-2 Vaccine Combines Immune Focusing and Self-assembling Nanoparticles to Elicit More Potent Protection

Written by The Wistar Institute on February 1, 2022. Posted in Press Releases.

PHILADELPHIA — (Feb. 1, 2022) — The first generation of COVID-19 vaccines have been highly effective, but also have limitations: their efficacy can wane without a booster shot, and they may be less effective against some variants. Now scientists at The Wistar Institute have developed a more targeted vaccine that, in animal studies, shows stronger, broader, and more durable protection in a single, low dose.

The vaccine combines three technologies – immune focusing, self-assembling nanoparticles, and DNA delivery – into a single platform for the first time. In addition to its other advantages, the vaccine could be stored at room temperature, making it potentially easier to transport to remote or developing locations than existing mRNA vaccines, which require specialized cold storage.

“This is among the first next-generation vaccines that will have more advanced features and broader protection,” said Daniel Kulp, Ph.D., associate professor in the Vaccine & Immunotherapy Center at The Wistar Institute and corresponding author of the study.

The paper, “Nucleic acid delivery of immune-focused SARS-CoV-2 nanoparticles drive rapid and potent immunogenicity capable of single-dose protection,” was published in the journal Cell Reports.

Existing vaccines include an unmodifided receptor binding domain of SARS-CoV-2 spike protein. The new vaccine includes a rationally engineered receptor binding domain using computational and structure-based design methodologies. The engineered receptor binding domain blocks ‘immune distracting’ sites and can therefore elicit stronger levels of protective, neutralizing antibodies.

Researchers then used naturally self-assembling proteins to form nanoparticles which display these highly engineered immunogens. By arranging themselves into structures that resemble an actual virus, the nanoparticles are more easily recognized by the immune system and transported to the germinal centers, where they activate B cells which produce protective antibodies.

Using nucleic acid vaccine delivery technology similar to mRNA, the nanoparticle vaccine is encoded in DNA and delivered into cells thereby giving genetic instructions for the body to build the immunogen internally. This is an advance over traditional vaccines that must be manufactured in specialized factories through complex vaccine production processes. In contrast to other vaccines, Dr. Kulp noted that one advantage of the DNA platform is that it doesn’t require refrigeration and it can also be quickly reformulated to target new variants.

In animal models, researchers found that the DNA delivered immune-focused nanoparticle vaccine produced much higher levels of neutralizing antibodies than the vaccine that wasn’t immune-focused.

“A difficulty with current vaccines is that neutralizing antibodies decline over time,” Kulp said. The nanoparticle vaccine produced durable responses after a single immunization out to six months in mice, unlike what we are seeing with current SARS-CoV-2 vaccines in people.

The ultimate test for SARS-CoV-2 vaccine candidates is protection from death in SARS-CoV-2 challenge experiments. The researchers found that in a lethal challenge model 100% of mice who received the immune-focused nanoparticle vaccine were protected from death with a single low dose. Most mice who received the standard, non-immune focused vaccine died within 10 days of challenge.

The vaccine assessment was conducted in both wild-type mice and mice that were genetically engineered to mimic human immune systems, he noted.

Even without being updated, the immune-focused vaccine showed a comparable level of antibody production to Delta, and other variants, Kulp said. That’s partly because of the immune focusing approach itself, he noted; in blocking parts of the receptive binding domain for the purpose of inhibiting non-neutralizing antibodies, it also blocks many of the areas affected by spike protein mutations. Studies on the Omicron variant are underway.

Researchers are seeking funding to begin human trials of the vaccine.

Co-author David B. Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center and the W.W. Smith Charitable Trust Professor in Cancer Research, at The Wistar Institute, said the vaccine could provide a needed step forward to improve protection against COVID-19.

“Current vaccine effects on reducing transmission of SARS-CoV-2 variants of concern including Delta and Omicron could be improved for their breadth of protection as well as their immune potency,” Weiner said. “This study demonstrates that using a nucleic acid approach combined with in vivo structural assembly of a glycan immune-focused nanoparticle drives single protection and neutralization against diverse variants of concern in a dose-sparing formulation. Additional studies of this vaccine approach for SARS-CoV-2 appear timely and important.”

Co-authors: Kylie M. Konrath, Kevin Liaw, Yuanhan Wu, Xizhou Zhu, Susanne N. Walker, Ziyang Xu, Neethu Chokkalingam, Nicholas J. Tursi, Mansi Purwar, Emma Reuschel, Drew Frase, Benjamin Fry, and Ami Patel from Wistar; Katherine Schultheis, Igor Maricic, Viviane M. Andrade, Kate E. Broderick, Laurent M.P.F. Humeau, and Trevor R.F. Smith from Inovio Pharmaceuticals; Himanshi Chawla and Max Crispin from the University of Southhampton; Jianqiu Du and Alan Moore from Indiana University; Jared Adolf-Bryfogle and Jesper Pallesen from the Institute for Protein Innovation; Matthew Sullivan from the University of Pennsylvania; and Christel Iffland from Ligand Pharmaceuticals.

Work supported by: Wistar Coronavirus Discovery Fund, CURE/PA Department of Health grant SAP# 4100083104, COVID/PA Department of Human Services grant SAP# 4100089371, NIH/NIAID CIVICs grant 75N93019C00051, Wistar SRA 16-4 / Inovio Pharmaceuticals, Indiana University.

Publication information: Nucleic acid delivery of immune-focused SARS-CoV-2 nanoparticles drive rapid and potent immunogenicity capable of single-dose protection, Cell Reports, 2022.

The Wistar Institute Hosts U.S. Department of Commerce Official Making Major Grant Announcements to Strengthen Workforce Pipelines in Philadelphia & Across the Nation

Written by The Wistar Institute on January 27, 2022. Posted in Press Releases.

Wistar is a finalist of the STEM Talent Challenge to create a new life science workforce training program to address Pennsylvania industry growth and demand for skilled workers.

U.S. Assistant Secretary of Commerce for Economic Development Alejandra Y. Castillo will make a major national grant announcement in support of locally-driven programs that train STEM-capable workforces across the country and create pathways for good-paying STEM jobs in Philadelphia and across the United States at an event on Thursday, January 27, 2022 in Philadelphia.

WHO:

Ms. Alejandra Y. Castillo
U.S. Assistant Secretary of Commerce for Economic Development
U.S. Department of Commerce

Ms. Mary Gay Scanlon
U.S. Congresswoman
Pennsylvania’s 5th District

Mr. Jim Kenney
Mayor
City of Philadelphia

Dr. Dario Altieri
President & CEO
The Wistar Institute

WHAT: Major grant announcement in support of locally-driven efforts to strengthen innovation workforce pipelines in Philadelphia and across the United States.

WHEN: Thursday, January 27, 2022; 11 a.m./EST

WHERE: The Wistar Institute; Media are welcome to attend and ask questions virtually.

REGISTRATION: Please use the link below to register: https://register.gotowebinar.com/register/9102191982375060492

###

The mission of the U.S. Economic Development Administration (EDA) is to lead the federal economic development agenda by promoting competitiveness and preparing the nation’s regions for growth and success in the worldwide economy. An agency within the U.S. Department of Commerce, EDA makes investments in economically distressed communities in order to create jobs for U.S. workers, promote American innovation, and accelerate long-term sustainable economic growth. To learn more about EDA, visit www.eda.gov.

Dr. Italo Tempera in the lab with two lab members

Wistar Scientists Identify Therapeutic Target for Epstein-Barr Virus

Written by The Wistar Institute on January 17, 2022. Posted in Press Releases.

PHILADELPHIA — (Jan. 17, 2022) — A new study by researchers at The Wistar Institute, an international biomedical research leader in cancer, immunology, infectious disease, and vaccine development, has identified a new potential pathway for developing therapeutics that target Epstein-Barr virus (EBV). They discovered that the way the EBV genome folds, and thereby expresses itself and causes disease, is more complex than researchers originally thought, and they identified molecules that could be targeted to disrupt this folding.

“We identified two cellular proteins that are important to folding the EBV genome.” said Italo Tempera, Ph.D., associate professor in the Gene Expression & Regulation Program at The Wistar Institute and corresponding author on the paper. “There are existing drugs that target one of these proteins. And our data suggests that if we use that drug on EBV infected cells, we have a way in which we can actually interfere with the folding. That means we can interfere in the way in which the EBV viral genome is functioning.”

EBV, which affects more than 90% of individuals worldwide, is a dynamic virus, meaning that it can change its gene expression. If certain viral genes are expressed, the virus infects B-cells and causes them to overmultiply, which is especially problematic in individuals with suppressed immune systems, such as transplant patients.

Tempera and his colleagues wanted to understand the mechanics behind how the virus manipulates its genetic expression. To do this, they used a modified DNA sequencing technique to examine how the genome folds under different conditions.

“The virus was clever to use the same machinery that regulates the conformation of the human genome to also regulate its own gene expression,” said Tempera. Specifically, the researchers found that EBV uses two proteins, CTCF and PARP1, that also play a role in the expression of the human genome.

PARP1 is already a target of the drug, olaparib (sold under the brand name Lynparza), which is used to treat patients with ovarian cancer. This new study suggests that the drug may have a use for treating EBV positive lymphomas, as well.

“Usually PARP1 is targeted in the context of DNA damage,” said Tempera. “Our paper shows that there is another role of PARP1 in the chromatin folding, so this suggests that maybe we can expand the way in which we can use this drug not only to interfere with DNA damage, but we also might interfere with DNA folding and gene expression, which is something that we are testing now in the lab.”

Co-authors: Sarah M. Morgan, Lisa Beatrice Caruso, Andrew Kossenkov, Sarah Boyle, Paul M. Lieberman, and Italo Tempera from The Wistar Institute; Hideki Tanizawa from University of Oregon; Michael Hulse from Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University; Jozef Madzo and Kelsey Keith from The Coriell Institute for Medical Research; Yinfei Tan from Fox Chase Cancer Center.

Work supported by: National Health Institutes (NIH) grant R01 AI130209.

Publication information: The Three-Dimensional Structure of Epstein-Barr Virus Genome Varies by Latency Type and Is Regulated by PARP1 Enzymatic Activity, Nature Communications, 2022. Online publication.

###

Portrait photos of Dr. Rahul Shinde, Dr. Mohamed Abdel-Mohsen, and Dr. Alessandro Gardini

The Wistar Institute Is Pleased to Announce the Promotion of Dr. Rahul Shinde to Assistant Professor, and the Promotions of Drs. Mohamed Abdel-Mohsen and Alessandro Gardini to Associate Professor

Written by The Wistar Institute on January 11, 2022. Posted in Featured News.

Wistar is honored these talented and accomplished scientists commit each day in their lab to bringing new and creative insights to cancer, immunology, and infectious disease research. Their original research makes them leaders in their fields and goes beyond scholarly achievement, to their belief in collaboration, and the creation of scientific symposia, and educational programs that expand their respective scientific fields. All promotions were effective as of January 1, 2022.

Congratulations to Dr. Rahul Shinde—Promoted to Assistant Professor

Dr. Shinde joined Wistar in June of 2019 as our first Caspar Wistar Fellow and was programmatically appointed with the Immunology Microenvironment and Metastasis Program. In his relatively short time at the Institute, Shinde established a productive laboratory, initiated numerous collaborations both in and out of Wistar, received independent NIH funding, and developed an innovative research program on the impact of the immune microenvironment in pancreatic cancer, one of the deadliest malignancies in humans. His promotion is a tangible recognition of this track record of academic excellence and a testament to the Caspar Wistar Fellow program as an innovative and successful mechanism to help foster the transition to research independence of meritorious early career investigators.

Congratulations to Dr. Mohamed Abdel-Mohsen—Promoted to Associate Professor

Dr. Abdel-Mohsen was recruited to Wistar in 2017 as a member of Vaccine and Immunotherapy Center. As a junior faculty at the Institute, Abdel-Mohsen quickly established himself as an undisputed research leader in multiple fields of investigation, with innovative and groundbreaking contributions in various aspects of HIV biology and therapy, mechanisms of immune recognition and glycomics. In his short time at Wistar, he was recognized with an impressive number of scholarly achievements, including publications in top-tier scientific literature, large extramural funding and speaking engagements at national and international venues.

Dr. Abdel-Mohsen’s energy, collaborative spirit, and engaging personality, all about the science, have made him a go-to person at our Institute, and a premiere colleague and collaborator in the broader Wistar-Penn campus.

Congratulations to Dr. Alessandro Gardini—Promoted to Associate Professor

Dr. Gardini joined the Institute in 2015, establishing a successful, internationally recognized and highly collaborative scientific program. He is a vital contributor of the Gene Expression and Regulation Program in our Cancer Center and has made seminal contributions to our understanding of novel transcriptional networks exploited in tumor development and progression. In addition to his scientific and scholarly achievements, published in top journals, Dr. Gardini has been a great ambassador of Wistar, launching an exciting Ph.D. exchange program with the University of Bologna, establishing productive research collaborations with our colleagues at the Helen F. Graham Cancer Center at Christiana Care Health and organizing a number of scientific and educational venues, including the GER Mini Symposium in 2017.

Wistar and Stanford Medicine to Begin Phase 2 Clinical Trial of VK-2019 in Patients with Epstein-Barr Virus (EBV)-Positive Advanced Nasopharyngeal Carcinoma

Written by The Wistar Institute on January 5, 2022. Posted in Press Releases.

PHILADELPHIA — (Jan. 5, 2022) — The Wistar Institute announces the initiation of a Phase 2 clinical study of VK-2019 in patients with advanced Epstein-Barr Virus (EBV)-positive nasopharyngeal carcinoma (NPC) and lymphoma. The study, led by researchers at the Stanford University School of Medicine, will enroll patients who have recurred or progressed following standard therapy or have not responded to prior therapy.

The open-label, single-group Phase 2 clinical trial will assess the safety and efficacy of VK-2019. Enrollment is expected to begin later this year. The Phase 2 trial is supported by interim results from the Phase 1 study in advanced NPC patients that showed favorable safety, tolerability, pharmacokinetic (PK) and biomarker results as well as preclinical data that underscore the promising potential for the treatment of EBV-positive cancers.

The principal investigator of the study is A. Dimitrios Colevas, M.D., professor of Medicine at Stanford Cancer Institute.

NPC, a type of head and neck cancer that develops in the nasopharynx, is a serious global health problem, particularly prevalent in East and Southeast Asia. More than 90,000 people are diagnosed with NPC worldwide each year. Platinum-based chemotherapy is currently the first-line treatment after recurrence or metastasis. However, the duration of response is typically less than six months. One unique aspect of this type of cancer is that NPC tumor cells are infected with EBV.

VK-2019 is an oral, small molecule inhibitor of the latent form of EBV that drives the proliferation of infected cells. VK-2019 was invented by researchers at The Wistar Institute, an international biomedical research leader in cancer, immunology, infectious diseases, and vaccine development. According to Paul M. Lieberman, Ph.D., Hilary Koprowski, M.D., Endowed Professor and program leader, Gene Expression & Regulation Program, at The Wistar Institute, VK-2019 inhibits the viral protein Epstein-Barr Nuclear Antigen-1 (EBNA1), known as the master regulator of EBV replication and maintenance.

“EBNA1 is expressed consistently in all EBV-related cancer and is essential for the cancer to grow,” said Lieberman. “By targeting EBNA1, which has a unique protein fold and is present only in the cancer cells, we have so far observed fewer side effects than we typically see with other cancer drugs.”

Lieberman heads Wistar’s Center for Chemical Biology and Translational Medicine, comprised of a team of researchers developing promising basic research findings into new therapeutics to fight disease, particularly cancer. He and the team worked for almost a decade to discover and develop VK-2019.

He added, “The good news is that if we can demonstrate that VK-2019 is safe and effective in patients with nasopharyngeal carcinoma, then it may be safe and effective for other EBV cancers including EBV-positive gastric carcinoma and lymphomas.”

“We are excited about the potential of VK-2019 in treating nasopharyngeal cancer,” said Troy Messick, Ph.D., senior staff scientist in the Lieberman lab. “VK-2019 is unique because it targets the underlying driver of growth of this head and neck cancer, namely EBV.”

Funding for this Phase 2 clinical trial is provided by a grant from the National Cancer Institute.

###

Progress Toward a Cure: A Conversation with Leading Wistar HIV Research Scientist on World AIDS Day

Written by The Wistar Institute on December 21, 2021. Posted in Featured News.

On the eve of World AIDS Day, we chat with trailblazing scientist Dr. Luis Montaner, Herbert Kean, M.D., Family Professor, and leader of the HIV Research Program at Wistar. On Dec. 1, tune in to hear him in person as part of the NIH World AIDS Day 2021 Virtual Event.

Q: Tell me about the National Institute of Health’s (NIH) World AIDS Day virtual event. Is this the first time you’ve taken part?

A: Yes, it is, and it coincides with the release of the national HIV/AIDS strategy. We are discussing the research priorities moving into the future. I’m part of a panel to discuss recommendations, and community engagement.

Q: Have you taken stock of your most meaningful accomplishments over the last year? Have you reflected on the Wistar HIV Program you’re building, the type of researchers you’re recruiting, and what this means?

A: The last year has been transformational because we were able to successfully renew our Delaney grant with a larger coalition of investigators and a larger budget than the first award. Community engagement has also developed to a much greater extent than what we had before. We also were able to recruit additional investigators into the HIV program with Drs. Amelia Escolano and Dan Claiborne. Wistar efforts also developed the infrastructure for bringing humanized mouse models of disease into our HIV Program, identified novel predictors of HIV control, and completed recruitment of a human trial testing a novel strategy of immunotherapy against HIV in spite of COVID-19. Last year was critical to creating a great foundation for the impact Wistar will have on the search for an HIV cure in the coming years.

Q: What does World AIDS Day mean to you?

A: World AIDS day is really a reminder that we still have a lot of unfinished business to address. Although therapy has made living with HIV a chronic disease, there is still global disparity in access to therapy.

In addition, the need to generate a cure remains. On one hand, World AIDS Day is a reminder that we still have added efforts to move forward to provide answers as to how best to reach a cure, but at the same time, it’s sort of a time to reflect and recognize our progress in moving cure-directed efforts forward.

Q: Tell me about this year’s theme Ending the HIV Epidemic: Equitable Access, Everyone’s Voice. How do you ensure community representation in the recruitment of your clinical trials? How do you equally include minorities in clinical trial representation?

A: Community engagement across all NIH efforts is a priority and is reflected in the focus of the NIH virtual discussion happening on 12/1.

We at Wistar have recognized that it’s an important feature of our efforts from the beginning. Community outreach in Philadelphia has been effective in bringing voices from all people living with HIV into the Wistar research fold. It is reflected in the Jonathan Lax lectures we’ve held for over 25 years, the Legacy Awards earlier this year in which we acknowledged our partners, and the development of a cure research-directed Community Advisory Board (CAB), which now directly convenes around our research. Bringing together Philadelphia FIGHT with our Community Advisory Board, we now have created a Community Engagement Group that we call the CEG. The perspective from community groups is different than the perspective of individual persons living with HIV (members of the CAB). But together, each bring a lot more voices into the research effort.

Q: Tell me a few of the successes you’ve had in the course of your career thus far and why they are important?

A: I think the biggest success is the development of coalition of researchers singularly focused towards a cure. Bringing together and growing a group that nurtures new investigators and advances seasoned investigators towards a common goal, is a great story.

Q: In latest news, a second person has been cured naturally by their own immune system. What does it mean for the HIV cure research that you’re doing, and future?

A: I think this case gives us all hope as it shows that our immune systems can overcome an established infection. We still have the open question as to how it happened – but the fact it did means we can reach towards that goal for all.

Q: You work closely with community partners to continue advancing research towards an HIV cure. Is there any person or people who taught you what community outreach means and how to do it? What did you learn from them? How did they teach you? What do you think you taught them?

A: A lot of times we get so invested in the research effort that we have to stand back to see it from the community perspective, from individuals living with HIV, and all affected populations. Persons living with HIV come from all walks of life including those with disparities in access to health care, economic challenges, class challenges that may include a whole series of life experiences including domestic violence, or other types of unique circumstances that has shaped how HIV affected their lives. The recent creation of a CAB bringing community input into our cure-directed efforts has taught me the power of individual experience when deciding how best to communicate with and/or work with community partners to advance research towards a cure.