Author: The Wistar Institute

Nobel Laureate Drew Weissman, M.D., Ph.D., Delivers 28th Annual Jonathan Lax Memorial Lecture at The Wistar Institute

Written by The Wistar Institute on July 10, 2024. Posted in Press Releases.

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CONTACT:
Darien Sutton
215-898-3988 | dsutton@wistar.org

PHILADELPHIA — (July 10th, 2024) — On Tuesday, July 16th at 6:30 pm EDT, Nobel Laureate in Medicine or Physiology Drew Weissman, M.D., Ph.D., — Roberts Family Professor in Vaccine Research, Director of Vaccine Research, and Director of the Institute for RNA Innovation at the University of Pennsylvania — delivers the 28th annual Jonathan Lax Memorial Lecture at The Wistar Institute in recognition of his outstanding contributions to HIV research. Dr. Weissman’s talk, “Development of novel therapies based on RNA: from COVID vaccines to anti-HIV strategies,” is open to the public both in-person at Wistar and virtually through an online live stream.

Dr. Weissman and his colleague Dr. Katalin Karikó received the 2023 Nobel Prize in Physiology or Medicine for their research on mRNA vaccine technology — technology vital to the development of the lifesaving COVID-19 vaccines that mitigated the worldwide pandemic. That same mRNA technology has opened the door to many different angles of approach to HIV cure research, which will be the subject of Dr. Weissman’s talk.

“I am honored to receive this award from my colleagues at The Wistar Institute in memory of such an inspiring figure as Jonathan Lax, whose dedication to helping those living with HIV is an example to every one of us,” said Weissman. “Although HIV has long presented a challenge to us biomedical researchers, I am grateful that my lab’s work on RNA has been able to make an impact in the all-important search for a cure.”

“Honoring a researcher with The Jonathan Lax Memorial Award is always a privilege for us, but this year, we are especially happy to have the opportunity to distinguish our neighbor, collaborator, and friend, Dr. Drew Weissman,” said Wistar’s Luis J. Montaner, D.V.M., D.Phil., the 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. “As a revolutionary RNA researcher whose work has paved the way for new approaches to overcoming HIV, Dr. Weissman’s research continues to improve upon our capabilities to understand and defeat HIV.”

The Wistar Institute and Philadelphia FIGHT established the Jonathan Lax Memorial Award Lecture after Mr. Lax’s death to honor his legacy by bringing distinguished speakers to a lay audience. Previous speakers include luminaries in the HIV/AIDS field such as Nobel Laureate Françoise Barré-Sinoussi, Ph.D., Professor Emeritus at the Institut Pasteur; Mike McCune, M.D., Ph.D., head of the HIV Frontiers Initiative and Biotechnology Accelerator Program of the Bill & Melinda Gates Foundation; and Anthony S. Fauci, M.D., former Director of the National Institute of Allergy and Infectious Diseases.

The 2024 lecture is free and open to a global audience. Register here for in-person attendance and register here for virtual attendance.

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

Revolutionizing Cancer Treatment: Wistar and Accelerated Biosciences Collaborate to Pioneer Transformative Immune Cell Therapies

Written by The Wistar Institute on July 10, 2024. Posted in Press Releases.

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CONTACT:
Darien Sutton
215-898-3988 | dsutton@wistar.org

PHILADELPHIA — (July 10, 2024) — The Wistar Institute (“Wistar”) is pleased to announce a research collaboration with Accelerated Biosciences Corp. (“Accelerated Bio”) aimed at creating a groundbreaking platform based on human trophoblast stem cells (hTSCs) to explore new immunotherapies that use Accelerated Bio’s proprietary technology. This collaboration has the potential to transform the field of allogeneic immunotherapies by generating various types of immune cells from hTSCs.

Accelerated Bio’s hTSC platform is the cornerstone of this collaboration. These hTSCs exhibit high plasticity and immune privilege, making them an ideal potential strategy for diverse medical and biotechnological applications — including drug discovery, therapy development, biomanufacturing, and toxicology testing. The hTSCs are ethically sourced, pre-implantation, and early-stage pluripotent stem cells.

Luis J. Montaner, D.V.M., D. Phil., Vice President of Scientific Operations and Herbert Kean, M.D., Family Professor at The Wistar Institute, expressed his enthusiasm about the collaboration: “Collaborating with Accelerated Bio aligns perfectly with Wistar’s research objectives to develop new strategies for immunotherapy based on our understanding of the human immune system. We are excited to explore the innate capabilities of Accelerated Bio’s hTSCs and harness their potential to engineer superior allogeneic cell therapies against various diseases such as HIV or cancer.”

Yuta Lee, CEO of Accelerated Bio, emphasized the advanced capabilities of the hTSC platform: “Our hTSC platform is not only the earliest ethically sourced pluripotent stem cell source available but also one of the most dynamic and versatile. This research collaboration with Wistar will enhance our understanding of hTSCs and demonstrate their potential to revolutionize the cell therapy industry.”

Through this collaboration, Wistar and Accelerated Biosciences aim to develop a more efficient method for creating engineered allogeneic immune cells for immunotherapy by reducing manufacturing complexities, costs, and therapeutic risks.

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About Accelerated Biosciences Corp.

Accelerated Bio is at the forefront of healthcare innovation, leveraging the groundbreaking potential of hTSCs to revolutionize precision medicine. Originating from an early and ethical source, hTSCs possess extraordinary abilities to perform the functions of various cell types with added genetic stability, natural immune privilege, and high expansion capacity. Accelerated Bio’s extensive, robust, and unencumbered intellectual property portfolio ensures the freedom to innovate for both Accelerated Bio and its partners. For more information, please visit www.acceleratedbio.com

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The Wistar Institute Recruits Jozef Madzo, Ph.D., as Director of Bioinformatics

Written by The Wistar Institute on July 1, 2024. Posted in Press Releases.

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CONTACT:
Darien Sutton
215-898-3988 | dsutton@wistar.org

PHILADELPHIA — (July 1, 2024) — The Wistar Institute is pleased to announce the appointment of Jozef Madzo, Ph.D., to the faculty as an assistant professor and Director of Bioinformatics. Dr. Madzo will lead and oversee Wistar’s bioinformatics projects & initiatives across a variety of advanced biomedical research programs.

As an experienced bioinformatician and established researcher, Dr. Madzo brings decades of experience in large-scale biomedical data analysis for research applications, including analysis of whole-genome, transcriptional, and epigenetic datasets. At Wistar, Dr. Madzo will oversee the bioinformatics pipeline that has become increasingly relevant to foundational biomedical research.

“The Wistar Institute is pleased to welcome Dr. Madzo to our faculty as Wistar’s Director of Bioinformatics,” said Dario Altieri, M.D., Wistar president and CEO, director of the Ellen and Ronald Caplan Cancer Center, and the Robert and Penny Fox Distinguished Professor. “More and more, foundational biomedical research requires robust bioinformatics support, and we at Wistar are excited to have the expertise and leadership of Dr. Madzo to advance our bioinformatics endeavors.”

The newly established Madzo Lab at Wistar will continue Dr. Madzo’s work in the epigenetics of cancer, which is the study of how genes’ expression can impact cancer’s characteristics. Specifically, Dr. Madzo studies how patterns in an epigenetic factor called DNA methylation — which refers to when methyl molecules are chemically incorporated DNA’s constituent molecules — affect cancer development & progression.

“I’ve always admired the exciting work at The Wistar Institute, so it’s a special opportunity and honor to join such stellar researchers,” said Dr. Madzo. “I look forward to joining my colleagues in their daily fight against cancer and disease by providing them with collaborative bioinformatics support.”

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Wistar President’s Society Members Gather for Special Event Featuring Dr. Paul Offit

Written by The Wistar Institute on June 27, 2024. Posted in Featured News.

The June 4, 2024 event recognized President’s Society members for their contributions to the Institute.

Nearly 100 steadfast members of Wistar’s President’s Society and honored guests gathered at The Wistar Institute to attend this year’s President’s Society Dinner for an evening of community and reflections on the scientific journey. Dr. Dario Altieri, Wistar President & CEO, welcomed attendees and emphasized the importance of their support. “You are investing in what is yet to come – discoveries that have the potential to change human health,” he explained.

The event featured Keynote Speaker Dr. Paul Offit, world-renowned virologist and director of the Vaccine Education Center at Children’s Hospital of Philadelphia (CHOP). Dr. Offit, who completed a fellowship in Dr. Walter Gerhard’s lab at Wistar during the 1980s, told the audience about his path to science, and the importance of his lab experience. He attributed his success as a scientist to the formative experience he had performing basic research at Wistar.

“I was here for five years because I was just overwhelmed with the prospect of doing science. How amazing it was to be able to pursue a career in basic science,” he explained. “It was unlike anything I’d done before … The researchers in the lab took it upon themselves to teach me how to think like a scientist, and work like a scientist.”

Later in his career, Dr. Offit collaborated with Wistar scientists on work that contributed to the development of RotaTeq, a vaccine that is used to protect against rotavirus infections. The vaccine is on the World Health Organization’s List of Essential Medicines.

Dr. Offit continued, “I just don’t know how much I can thank … all the people that were in the laboratory that were devoted to making me the scientist that I am.” He then took a moment to acknowledge Dr. Gerhard, who had returned to Wistar for the event.

Dr. Offit, who has authored more than 13 books, provided attendees with a signed copy of his latest, Tell Me When It’s Over: An Insider’s Guide to Deciphering Covid Myths and Navigating Our Post-Pandemic World.

The President’s Society Dinner is an annual event celebrating members of Wistar’s President’s Society, a dedicated community of supporters who provide essential, annual funding to The Wistar Institute. Visit us online to learn more about the benefits of becoming a member.

To view a gallery of the event, please visit here.

Wistar’s Dr. Noam Auslander Awarded $600K V Foundation Grant to Identify Connections between Gut Microbial Genes & Melanoma Immunotherapy

Written by The Wistar Institute on June 27, 2024. Posted in Press Releases.

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CONTACT:
Darien Sutton
215-898-3988 | dsutton@wistar.org

Dr. Auslander’s project will investigate the effects of microbial proteins on immunotherapy responses

PHILADELPHIA — (Thursday, June 27, 2024) — The Wistar Institute’s Noam Auslander, Ph.D., assistant professor in the Molecular and Cellular Oncogenesis Program at the Ellen and Ronald Caplan Cancer Center, was awarded a $600,000 Women Scientists Innovation Award for Cancer Research grant from the V Foundation for Cancer Research to support the next three years of her research, which will use proteins of gut bacteria to predict immunotherapy benefit in melanoma. Dr. Auslander plans to analyze microbial proteins from the guts of patients to determine how they may drive melanoma immune responses, with the ultimate goal of improving the clinical benefits of immunotherapy.

“The V Foundation plays a crucial role in supporting and enabling transformative cancer research,” said Noam Auslander. “This prestigious award allows us to use computational biology methods to gain insights from complex data sets that can allow clinically impactful discoveries. Our goal through this project is to determine how patterns in the gut microbiome of melanoma patients determine immunotherapy responses. The V Foundation’s philanthropic support allows us to dig deep into this question using different computational methods, and, with the support from our clinician and experimental collaborators, potentially improve future clinical decisions and treatment outcomes.”

The V Foundation for Cancer Research was founded in 1993 by the late Jim Valvano, ESPN broadcaster and renowned basketball coach, and has allocated more than $353 million in grants for cancer research across the nation. By supporting the most promising cancer research projects from exceptional scientists of diverse backgrounds, The V Foundation has empowered investigations into cancer types of all stages — from the lab to the clinic.

“The V Foundation is honored to support Dr. Auslander’s innovative cancer research addressing a major unmet need in predicting responses to melanoma treatment. We look forward to seeing the novel findings her work will uncover and the impact it will have on patients in the future,” said Kara Coleman, Ph.D., Vice President of Research and Grants Administration at the V Foundation.

Dr. Auslander’s high-impact data research in melanoma immunotherapy happened due to generous V Foundation support.

“Dr. Auslander’s research identifies valuable patterns in human biology through large-scale data analysis with advanced computational techniques,” said Dario C. Altieri, M.D., Wistar president and CEO, director of the Ellen and Ronald Caplan Cancer Center, and the Robert and Penny Fox Distinguished Professor. “By investing in the burgeoning field of machine learning, this grant from the V Foundation accelerates the use of machine learning in transformative science.”

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Why this Wistar Scientist sees hope for an HIV cure

Written by The Wistar Institute on June 20, 2024. Posted in Featured News.

Dr. Luis J. Montaner, D.V.M., D. Phil., is the Herbert Kean, M.D., Family Professor; vice president of Scientific Operations; associate director for Shared Resources at the Ellen and Ronald Caplan Cancer Center; director of the HIV-1 Immunopathogenesis Laboratory; and leader of the HIV Research Program, Vaccine & Immunotherapy Center, at The Wistar Institute.

He leads the BEAT-HIV Delaney Collaboratory and investigates new strategies that boost the natural function of the immune system to combat virus-associated diseases like HIV.

Give us a primer on human immunodeficiency virus: What do scientists know about how HIV works, and what questions are still being investigated?

We, as a field, have learned how to design drug therapies to control but not eradicate HIV. The HIV virus can introduce mutations into its replication cycle and acquire resistance to single-drug therapies. It’s why three drugs are used in current combination antiretroviral therapy (ART) because it’s much more difficult to develop mutations against three drugs at once.

Controlling HIV replication does not logically extend to a cure with the current therapies. The virus persists, and interestingly, it retains features that reflect how soon a person started ART. For instance, if you had a particular viral replication level and an immunological setpoint when you started antiretroviral therapy, it would return to that point if you ever stopped — even if you’d been on therapy for 15+ years. The HIV research field as a whole has also learned how the virus persists in a person after they start antiretroviral therapy, and how to measure persistence changes in the blood to then evaluate if cure-directed strategies may work.

However, even if you have a treatment that successfully attacks the HIV virus hiding in the blood, that might not be enough — because the virus’ latent reservoirs extend beyond what we call the “blood compartment.” Researchers need to ensure that any strategy can reach all tissue compartments, such as the brain, liver, muscle, bone, etc., as HIV can reside within immune cells in all organs.

Where does your optimism for finding a cure for HIV come from?

If you think about the phases of HIV research, as a field, we have achieved success on several fronts, and we trust the same will be true for an HIV cure. First, a brief history of HIV/AIDS: scientists and doctors started with the quest to ensure HIV diagnosis and secure our blood banks. We then shifted to preventing the high death rate by developing therapies that could prevent viral replication and allow the immune system to recover.

Then came the phase where we have been for a while: the search for a vaccine. It’s only recently that we’ve added cure-directed research as a clear objective, which follows from the extraordinary cases in which individuals were cured because of their cancer therapy.

Although the cancer treatments associated with HIV cures can also be fatal — and are not safe to give to persons living with HIV when compared to the safety of life-long antiretroviral therapy — the existence of these cases prove that a cure is possible.

The HIV cure research field is now looking for strategies toward one of two outcomes: either eradicating the virus within a person on therapy and stably suppressing viral replication; or achieving long-term control without the continued use of antiviral therapy. We are still in the early days of this effort, but the outlook is promising.

If you think about it, we’ve been addressing the HIV global pandemic for more than 30 years. The breakthroughs in antiretroviral therapy came about 10-12 years after we started research efforts, and now we’re only at the beginning years of the cure-directed effort, which continues to grow. So, the investment in cure is increasing — which means the expertise behind and opportunity for the discovery of a cure strategy also increases.

We’re advancing our search for a cure by bringing teams together like never before. A good example of this new coalition effort across geography and institutions under one large project is the BEAT-HIV Delaney Collaboratory. Working together as a team is a lot more effective.

What does it look like to collaborate with groups like Philadelphia FIGHT, which extends HIV research into local communities?

If you’re going to do research on a particular condition, you’d best do it with the awareness, input, and approval of people living with that condition. When I started at Wistar in 1995, I initiated outreach to the community. We now have one of the longest-lasting community engagement programs anywhere, and it’s focused on uniting HIV researchers with persons living with HIV. We’ve become a model for other cities.

What’s different about our model is how we’ve built a community engagement group that includes not only a community advisory board of individuals, but also Philadelphia FIGHT, a comprehensive health services organization that cares for people living with HIV by working directly within and for the community. We meet with both the community advisory board and Philadelphia FIGHT members regularly to create an environment where community members are part of the team. That sense of equity, and the weight of participation, empowers everybody. As our community members often say, they want to be “in the kitchen helping to create the cure — not outside being served after the cooking is complete.” From the beginning, we bring the community members to the table where they are part of the team.

After nearly three decades, why do you choose to continue your work toward curing HIV at Wistar?

I’m here because I see local and global opportunities for the future of our program. Opportunities ahead are just as impactful and interesting as when I walked through the door 29 years ago. The Wistar Institute has a long and storied history as a global leader in biomedical research and is unique in its ability to support the vision of a principal investigator as they grow their program.

If you want to develop a focused program and collaborate on a global scale — then Wistar outperforms anyone else.

For more information, email comm-marketing@wistar.org.

The Wistar Institute Receives $10 Million Donation

Written by The Wistar Institute on June 18, 2024. Posted in Press Releases.

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CONTACT:
Darien Sutton
215-898-3988 | dsutton@wistar.org

Brings Lead gift to $30 million – Largest Contribution in Wistar’s History

PHILADELPHIA — (June 18, 2024) — The Wistar Institute received a $10 million donation from an anonymous donor who previously committed $20 million to support Wistar’s new Center for Advanced Therapeutics. This now $30 million gift to Wistar’s Bold Science//Global Impact Campaign is the largest in the Institute’s history and enables Wistar to fund the design and construction of its new Center for Advanced Therapeutics, a cornerstone of the Institute’s strategic plan.

“This exceptional gift is a testament to the promise and hope of biomedical research in conquering human diseases. The time is now to foster freedom to discover, embrace innovation and advance the most promising research findings from the laboratory benches to patients in the clinic,” said Wistar President and CEO Dario C. Altieri, M.D.

The new Center for Advanced Therapeutics represents the next step in the evolution of Wistar Science, a unique engine for cross-disciplinary collaboration, scientific innovation, and impactful public-private partnerships to pursue the medicines of tomorrow.

“I agreed to chair this campaign because I truly believe Wistar has the power to make a difference for all mankind,” said Ronald Caplan, chair of the Bold Science//Global Impact Campaign. “Generous gifts like this enable Wistar researchers to pursue discoveries that can lead to breakthrough cures, and this new Center for Advanced Therapeutics will allow us to accomplish just that. It’s an honor to be part of this work and to contribute to the future of the Institution.” Ellen and Ron Caplan made a separate generous $10 million gift to the Campaign in 2022.

Emphasis will be placed on both next-generation immunotherapies as well as small molecule therapeutics to “drug-the-undruggable,” with a laser focus on unmet medical needs and hard-to-treat conditions in cancer and infectious diseases. Relying on Wistar’s nationally recognized collaborative and multidisciplinary framework, the Center will tackle critical and unexplored research areas of enormous therapeutic potential such as the diversity of B cell and T cell repertoires, novel drug-target interfaces, and groundbreaking vaccine platforms.

“Wistar is a key contributor to the life science sector in Philadelphia, and an engine for new scientific knowledge, medical breakthroughs and workforce development in our region,” said Richard M. Horowitz, chairman and CEO of RAF Industries, Inc., and chair of Wistar’s Board of Trustees. “This investment positions Wistar to pursue even greater advances in research and fully realize its potential to translate those discoveries into solutions that improve human health and ultimately save lives.”

Wistar will begin construction on the new Center at its landmark facility in University City, Philadelphia, in the summer of 2024. The new facility will provide a comprehensive, state-of-the-art, open-floor plan research facility, embodying the culture of collaboration and synergy that is the hallmark of The Wistar Institute and its scientists.

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Research in the Classroom: Wistar and Collaborators Enhance Experiential Learning in The Life Science Classrooms of G.W. Carver High School

Written by The Wistar Institute on June 10, 2024. Posted in Featured News.

[pictured: George Washington Carver High School students observe Wistar’s Andrew Milcarek, Ph.D. in the lab]

Philadelphia’s George Washington Carver High School of Engineering and Science is a criteria-based admission school that enrolls students with demonstrated excellence and ambition, many of whom have a strong interest in various STEM fields. Thanks to a collaboration between Heights Philadelphia and The Wistar Institute, with vital support from Philadelphia-based gene therapy company Spark® Therapeutics, the students in Mr. Latchford’s 9th grade Science Research classroom participated in hands-on lab activities that complement the current curriculum focusing on the scientific method.

To support this program, Wistar’s Jason Diaz, Ph.D. — director of education & inclusive excellence and assistant professor in the Hubert J.P. Schoemaker Education and Training Center — loads up his car with Wistar equipment and heads to Carver, where he becomes “Dr. D.” to the room full of eager science champions. At Carver, Dr. Diaz brings the authentic research of The Wistar Institute straight into the classroom, where, as the educational research shows, students can develop identities as scientists and become not only comfortable with but enthusiastic about pursuing careers in science. By reaching out to more students at earlier stages in their high school careers, Wistar’s Hubert J.P. Schoemaker Education and Training Center aims to share the opportunities of science with Philadelphia communities.

Carver is an ideal high school to implement this program, according to Dr. Diaz and his counterparts at Heights; as both a criteria-based admission school as well as a school comprised mostly of students from populations underrepresented in the life sciences, the program engages and challenges students who might not have otherwise thought of careers in science as “for them.” Building on the successes of a similar pilot program last year, this year’s collaboration between Heights and Wistar received additional support from Spark Therapeutics, who aim to foster robust opportunities for Philadelphians to find meaningful careers in the life science sector. To further encourage Philadelphia’s future scientists, the program has also brought Carver students to tour The Wistar Institute’s laboratories, where they saw a professional research environment first-hand — and perhaps were inspired to apply to Wistar’s Summer High School Program in Biomedical Research.

“At Carver, we have some of the smartest students in the city,” said assistant principal Ms. Elizabeth Curry, “But to get them thinking about applying their talents — in their studies, in their future plans, and, eventually, in their career paths — we need to engage their interest level where they are. That’s why giving ninth graders hands-on education with real research equipment is so important.”

Dr. D.’s students agree. “I think of myself as a science enthusiast,” said one student, reflecting on his experience using the gel electrophoresis device that had been brought into the classroom for that day’s instruction. “I’m able to work with real scientific equipment and conduct an experiment — I get to say that I used these tools just like a real scientist.”

One of the students showed a strong interest in how this Wistar programming aligns with her ambitions: “My goal is to become an anesthesiologist, and hands-on research lessons like this get me thinking and actually doing the science — lessons are fine, but I enjoy the activities,” she said. “I feel like it really opens the door for what I want to do.”

Many students were captivated by the practical approach. “It’s not every day that you get to see or use this equipment, and I enjoyed learning how specific and precise you need to be when you do use it. I appreciate the opportunity, because I know it’s a cool experience not a lot of students get to have.”

The classes ended with words of encouragement and gratitude from Spark’s representatives, who spoke to the legacy scientific advances that are an integral part of Philadelphia’s history and its economy.

“At Spark, we work with exciting and inspirational technologies every day, but we’re here at Carver because it’s just as inspiring to see students like you engage with research in that same spirit of curiosity that drives our work,” said Candace Edwards, Spark’s Associate Director of Communications.

As the final bell of the afternoon rang and the students filed out into the sunny April day, Dr. Diaz regrouped with Mr. Latchford to review the day’s success and review plans for future lessons powered by the investments made by all three organizations. In the words of Carver’s principal, Dr. Darryl Johnson, the key to the success of Carver’s student body is collaborations like those with Wistar: “Relationships are the new currency. If you want to be a successful school, then you need to cultivate intentional relationships.” With the support of Heights and Spark Therapeutics, The Wistar Institute will continue to do just that by working toward a Philadelphia where high school students feel empowered and confident to pursue scientific opportunities that lead them through the rest of their schooling and into scientific careers.

Wistar Scientists Develop Novel Antibody Treatment for Kidney Cancer

Written by The Wistar Institute on June 4, 2024. Posted in Press Releases.

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CONTACT:
Darien Sutton
215-898-3988 | dsutton@wistar.org

PHILADELPHIA — (June 04, 2024) — Advanced clear cell renal cell carcinoma (ccRCC) is a deadly form of kidney cancer with few treatment options; even with new immunotherapies, only around one in 10 patients ultimately survive.

Antibody therapies called bispecific T cell engagers (BTEs) have emerged as effective treatments for some blood cancers but have been more difficult to develop for solid tumors. While clinically successful, first-generation BTEs suffer a short half-life. Now, Wistar scientists have built upon BTE technology to develop new and improved recombinant and synthetic DNA versions of therapeutic antibodies that target CA9, called Persistent Multivalent T Cell Engager (CA9-PMTE), that shows promise in pre-clinical models as a potent, long-lasting treatment against ccRCC.

In this study, the researchers also demonstrated that the more potent therapy could be delivered using synthetic DNA, which allows therapeutic production directly in patients. “The big takeaway is that there may one day be a promising new therapy for kidney cancer that has a mechanism of action that would be compatible for combination with checkpoint inhibitors, which is the current therapy of choice for this type of cancer,” said first author Ryan O’Connell, a predoctoral trainee in the Weiner lab at The Wistar Institute’s Vaccine & Immunotherapy Center. “What’s more, this improved bispecific antibody is outperforming the traditional bispecific antibodies in our studies, both in efficacy for treating ccRCC and in the approach’s ability to last much longer in the body, thus potentially being treatment-sparing.”

One reason clear cell renal cell carcinoma is so difficult to treat is because it is a so-called “cold” tumor — one in which cancer cells are unrecognizable by immune cells. This means that killer T-cells — a type of immune cell that seeks out and destroys diseased cells and cancers — are unable to recognize the tumor cells. As a result, immunotherapies that work by enhancing the T cells’ killing potency without improving their ability to bind to their targets are less effective against cold tumors.

These new forms of bispecific T cell engagers overcome this problem by functioning like “double-sided tape,” O’Connell explains. One side of the drug molecule binds to the T-cell, while the other side is engineered to bind to the specific type of tumor cell being treated; these molecules are “bispecific” because each end of the molecule is specific to one of two targets, the T cells and the cancer cells. This empowers the T-cells to attack and kill the cancer — even in cold tumors — by supplementing their ability to bind to the tumor.

But while BTEs are a promising new therapy for many difficult-to-treat cancers, they do have some limitations, including a short half-life (which is how long it takes for the active dose of a drug in one’s body to decrease by 50%). Most BTE drugs break down quickly, sometimes within a matter of hours, which means they are only effective for a short time.

In preclinical models, the team tested the efficacy of novelly designed anti-ccRCC BTE variants developed to enhance the interactions between T cells and the targeted cancer. These were developed to be delivered using synthetic DNA technology — a method of delivery that allows the body to assemble the desired drug design from DNA-based code themselves. The researchers compared traditional BTEs with a newer format design termed persistent BTEs (PBTEs), which have a longer half-life but use the same targeting system as older BTEs. They found that, while the initial PBTEs did last longer than the traditional BTEs, the new design reduced the overall anticancer potency.

The research team then created a new molecule by taking an existing PBTE and adding additional binding domains to better “see” and bind to the cancer. This novel, alternative design — called a persistent multivalent T cell engager (PMTE) — proved to be highly potent while also maintaining a longer half-life than the traditional BTE design.

Senior author David Weiner, Ph.D., executive vice president of The Wistar Institute and director of the Vaccine & Immunotherapy Center, said the new format represents the potential for an important new tool for enhancing cancer therapy.

“Bispecifics in general are an important technology that offer significant advantages in on-target anticancer potency,” he says. “The new PMTEs appear not only more effective at binding to tumor cells and killing the cancer, but they also require a much lower dose and, we have reason to believe, a lower frequency of therapy — which could potentially translate to improved outcomes and a better patient experience at a lower cost.”

The researchers are now studying these new PMTEs in combination with other immunotherapies as well as expanding designs to additional difficult-to-treat cancers.

Co-authors: Ryan P. O’Connell and Daniel Park of The Perelman School of Medicine at the University of Pennsylvania and The Wistar Institute; Kevin Liaw, Pratik S. Bhojnagarwala, Devivasha Bordoloi, Nicholas Shupin, Danie Kulp, and David B. Weiner of The Wistar Institute; Nils Wellhausen of The Center for Cellular Immunotherapies at the Perelman School of Medicine; Carl H. June of The Center for Cellular Immunotherapies at the Perelman School of Medicine and The Parker Institute for Cancer Immunotherapy at The University of Pennsylvania; and Chris Chuckran of LUMICKS

Work supported by: National Institutes of Health grants T32 CA11529915 and P30 CA010815; The Jill and Mark Fishman Foundation; the W.W. Smith Charitable Trust; and Inovio Pharmaceuticals.

Publication information: “Format-tuning of in vivo-launched bispecific T cell engager enhances efficacy against renal cell carcinoma,” published in Journal for Immunotherapy of Cancer (JITC)

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Wistar Research Identifies Mechanisms for Selective Multiple Sclerosis Treatment Strategy

Written by The Wistar Institute on May 28, 2024. Posted in Press Releases.

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CONTACT:
Darien Sutton
215-898-3988 | dsutton@wistar.org

Wistar’s Lieberman lab stopped inflammatory signaling and immune response in lab samples

PHILADELPHIA — (May 28, 2024) — The Wistar Institute’s Paul M. Lieberman, Ph.D., and lab team led by senior staff scientist and first author, Samantha Soldan, Ph.D., have demonstrated how B cells infected with the Epstein-Barr virus (EBV) can contribute to a pathogenic, inflammatory phenotype that contributes to multiple sclerosis (MS); the group has also shown how these problematic B cells can be selectively targeted in a way that reduces the damaging autoimmune response of multiple sclerosis. The lab’s findings were published in Nature Microbiology in the paper, “Multiple sclerosis patient derived spontaneous B cells have distinct EBV and host gene expression profiles in active disease.”

EBV — a usually inactive, or latent, herpesvirus — affects most of the human population; more than 90% of people carry the virus as a passive, typically symptomless infection. However, EBV infection has been linked to several diseases, including MS: an incurable, chronic autoimmune disease that causes the body’s immune system to attack the myelin sheath of neurons in the brain and nervous system. Because myelin sheathing facilitates fast nervous system signaling (the fatty insulation of myelin along a neuron’s axon allows electrical impulses to travel through neuronal networks faster), its degradation can cause a wide variety of symptoms in both type and severity that may include motor control disruption, sensory issues, and speech difficulties.

Though researchers know that EBV can contribute to the development of MS, the exact mechanisms by which it does so aren’t completely understood. The Lieberman lab, in seeking to understand how EBV contributes to the development of MS, collaborated with Steven Jacobson, Ph.D., of the Neuroimmunology Branch at the National Institute of Neurological Disorders and Stroke, who contributed cell line samples from patients. The research team analyzed spontaneous lymphoblastoid cell line (SLCL) cell samples from a healthy control group; a group of patients with active MS (as opposed to so-called stable MS; the disease is characterized by unpredictable periods of flare-ups and eased symptoms); and a group of patients with stable MS.

B cells are crucial cells of the immune system that help regulate the body’s immune responses; they have also been implicated in autoimmune conditions due to their role as mediators of which biological signals warrant immune response. And B cells, when infected with EBV, become immortalized — that is, the cells are no longer constrained by senescence, so they can continue to divide an indefinite number of times — as “lymphoblastoid cell lines,” or LCLs. This immortalized B cell state can occur spontaneously within the body as a result of EBV infection, which is how the Lieberman lab was able to extract immortalized SLCL samples for study from the different patient groups.

Having obtained the matched samples, Dr. Lieberman and his team conducted genetic analyses of the SLCLs and confirmed that the MS-positive sample groups showed greater expression of genes associated with lytic EBV (“lytic” describes when latent viruses like EBV become active); they also saw increased inflammatory signaling and expression of the FOXP1 protein, the latter of which was shown to promote lytic EBV gene expression. As a whole, the group’s findings suggested a mechanism of lytic EBV in MS that promoted inflammation and disease.

Diving further, Lieberman’s group tested several antiviral compounds on all SLCL groups and found that one, TAF, reduced lytic EBV gene expression without killing the cells. TAF also significantly reduced the expression of inflammatory cytokines like IL-6 in the SLCLs from the patients with active MS. Finally, when cultured SLCLs from active MS, stable MS, and controls were administered TAF in the presence of antiviral T cells, the T cell response (a major factor in the autoimmune dysfunction of MS) was reduced in SLCLs from patients with MS but not reduced in the control SLCLs — an indication that TAF treatment has potential as a selectively cytotoxic anti-lytic treatment for MS.

“Our work with these SLCLs shows that the problematic inflammation signaling from lytic EBV can be selectively targeted in a way that demonstrably reduces damaging immune responses,” said Dr. Lieberman. “We’re excited about expanding this concept further; we have the potential to see whether TAF or other inhibitors of EBV might be a viable treatment for multiple sclerosis that can stop the autoimmune damage without causing wide-ranging and dangerous cell death.”

Co-authors: Samantha S. Soldan, Chenhe Su, Leena Yoon, Toshitha Kannan, Urvi Zankharia, Rishi J. Patel, Jayaraju Dheekollu, Olga Vladimirova, Jack Dowling, Natalie Brown, Andrew Kossenkov, Daniel E. Schäffer, Noam Auslander, and Paul M. Lieberman of The Wistar Institute; Maria Chiara Monaco and Steven Jacobson of the Neuroimmunology Branch at the National Institute of Neurological Disorders and Stroke; Jack Dowling and Simon Thebault of the Perelman School of Medicine; Annaliese Clauze, Frances Andrada, and Joan Ohayon of the Neuroimmunology Clinic at the National Institute of Neurological Disorders and Stroke; and Andries Feder and Paul J. Planet of the Children’s Hospital of Philadelphia.

Work supported by: This work was supported by grants from the National Institutes of Health (R01 CA093606, R01 AI153508, R01DE017336 to PML, the Wistar Cancer Center Core Grant P30 CA010815), and the Department of Defense (HT9425-23-1-1049 Log#MS220073). The funders had no role in study design; data collection and analysis; decision to publish; or preparation of the manuscript.

Publication information: “Multiple sclerosis patient derived spontaneous B cells have distinct EBV and host gene expression profiles in active disease,” from Nature Microbiology

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