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Author: The Wistar Institute

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

[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

PRESS RELEASE

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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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


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Wistar Research Identifies Mechanisms for Selective Multiple Sclerosis Treatment Strategy

PRESS RELEASE
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

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

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Award-Winning Biotech Program Begins Another Recruitment to Connect Philadelphians with Quality Jobs in the Region’s Rapidly Growing Life Science Sector

The West Philadelphia Skills Initiative, The Wistar Institute, PIDC, The Chamber of Commerce for Greater Philadelphia, Iovance Biotherapeutics, and Integral Molecular Began Joint Recruitment May 21

Organizations in Greater Philadelphia’s life sciences ecosystem are collaborating again to connect more Philadelphians with meaningful career opportunities in one of the region’s fastest-growing industries through a new recruitment for a biotech training program.

This collaborative recruitment for the “Biomedical Technician Training (BTT) Program,” a first of its kind in the region, aims to connect Philadelphians from underserved communities who hold a high school diploma or equivalent to employment with local life science companies.

Recruitment for the Program began May 21 and goes through June 4. The application and additional program information can be found on The Navy Yard website at navyyard.org/skills.

For the first time in this award-winning program, two life science companies, Iovance Biotherapeutics (located at the Navy Yard) and Integral Molecular (located in University City), will be participating in the same recruitment. Upon successful completion of the training program, applicants will have an opportunity to interview for open positions with Iovance Biotherapeutics or Integral Molecular with roles starting at $21/hour.

“The life science industry is full of potential—for cures, jobs, economic growth, and hope,” shared Cait Garozzo, Executive Director of the West Philadelphia Skills Initiative. “Collaboration and iteration are crucial to make these possibilities a reality. By incorporating a second employer, Integral Molecular, we are able to expand on the history of success that we have seen with Iovance Biotherapeutics and connect even more Philadelphians to life-changing jobs at both life science hubs, the Navy Yard and University City.”

PIDC‘s Navy Yard Skills Initiative, a workforce development training program, created with West Philadelphia Skills Initiative to address the talent needs of the employers located at the Navy Yard, has been crucial in engaging its life science employers to create non-traditional pathways into cell and gene therapy careers, including at Iovance. Currently, the Navy Yard has nearly one million square feet of life sciences lab, production, and office space and 4 million square feet planned.

“This will be the 13th overall Navy Yard Skills Initiative recruitment and fourth life sciences-specific recruitment,” said Kate McNamara, PIDC’s Executive Vice President at the Navy Yard. “Through these partnerships, we have been able to connect nearly 120 Philadelphians to well-paying jobs at Navy Yard companies. As life sciences grows at the Navy Yard and in the city, it is paramount that we continue to make these investments in innovative workforce development programs. Funding secured with the help of Congresswoman Mary Gay Scanlon and a commitment from the Ensemble/Mosaic Navy Yard Building Better Foundation have been integral in growing our workforce development program at the Navy Yard.”

“In this fifth cohort of our BTT Program with the West Philadelphia Skills Initiative, we are excited to train Philadelphia residents for job opportunities with Integral Molecular and Iovance Biotherapeutics – two employers fueling the life science sector here in Philadelphia,” said Dr. Kristy Shuda McGuire, Dean of Biomedical Studies in the Hubert J.P. Schoemaker Education and Training Center at The Wistar Institute. “It’s critical our programs offer the skills our life science employers are looking for, whether that is a cutting-edge university or research institute lab, or a pharmaceutical or biotech company. As strong collaborators, we make sure to keep up with what the industry needs, and we’re excited to be doing this in a city that is a growing hub for the life sciences.”

“We’ve valued a longstanding partnership with Wistar’s BTT Program and have consistently admired their dedication to training students to have the necessary skills for success in biotech,” said Dr. Benjamin Doranz, CEO, Integral Molecular. “At Integral Molecular, we are expanding and transitioning to a production phase for many of our offerings. We look forward to a close collaboration with the BTT Program to recruit members of the Philadelphia community for vital roles in our laboratories.”

“Iovance is honored to host our third cohort of the Biomedical Technician Training Program. We look forward to continuing our collaboration with Wistar, the West Philadelphia Skills Initiative, the Chamber of Commerce, and PIDC to build deep, diverse life sciences talent pipelines across Greater Philadelphia and beyond,”said Jamie Crawford, Vice President, Commercial Manufacturing, Iovance Biotherapeutics, Inc.

“The announcement of this newest Biomedical Technician Training Program is excellent evidence of the collaboration that exists in Greater Philadelphia, the strength of the training, interest and involvement of employer partners, and ability to scale the Program to meet the needs of our region’s rapidly growing life science ecosystem,” said Nikki Pumphrey, Vice President, Talent and Workforce, Chamber of Commerce for Greater Philadelphia.

Recruitment & Program Information

  • Recruitment Dates: May 21 – June 4
  • Applicant Requirements: Applicants must be a Philadelphia resident, 18 years of age or older, hold a high school diploma or GED, test at a 12th grade level in reading, literacy, and math, and provide proof of having full COVID-19 vaccination by June 12
  • Where to apply: navyyard.org/skills

The 24-week paid training Program begins with 11 weeks of evening classes at The Wistar Institute focused on preparing participants with a foundation in cellular and molecular biology as applicable to the life science industry. After the first 11 weeks, participants will take part in a full-time, hands-on laboratory orientation at The Wistar Institute before transitioning to externships at the Iovance iCTC (Cell Therapy Center) at the Navy Yard or Integral Molecular in University City.

Throughout the 24-week program, the West Philadelphia Skills Initiative will support participants by offering professional development courses and coaching.

Select candidates who complete the program may interview for a full-time position at Iovance Biotherapeutics or Integral Molecular.

About the West Philadelphia Skills Initiative

The West Philadelphia Skills Initiative (WPSI) is one of the nation’s most successful workforce development organizations. For over 10 years, WPSI has solidified its role as one of the highest-performing workforce intermediaries in the country by building customized talent solutions that bridge the divide between unemployed Philadelphians seeking opportunity and employers seeking talent. WPSI focuses on professional development and career coaching for adults. www.philadelphiaskills.org

About The Wistar Institute

The Wistar Institute, the first independent, nonprofit biomedical research institute in the United States, marshals the talents of an international team of outstanding scientists through a culture of biomedical collaboration and innovation. Wistar scientists are focused on solving some of the world’s most challenging and important problems in the fields of cancer, infectious disease, and immunology. Wistar has been producing groundbreaking advances in world health for more than a century, consistent with its legacy of leadership in biomedical research and a track record of life-saving contributions in immunology and cell biology. Wistar’s Hubert J. P. Schoemaker Education and Training Center brings together education programs for high school, undergraduate and graduate students as well as postdoctoral fellows, with its expanding pre-apprenticeship and apprenticeship training, including the Fox Biomedical Research Technician (BRT) Apprenticeship. www.wistar.org

Media Contact: Steve Schneible (sschneible@wistar.org)

About PIDC and the Philadelphia Navy Yard

PIDC is Philadelphia’s public-private economic development corporation. Since acquiring the 1,200-acre site from the federal government in 2000, PIDC has been the master developer and site operator of the Navy Yard. PIDC’s mission—to spur investment, support business growth, and facilitate developments that create jobs, revitalize neighborhoods, and drive growth to every corner of Philadelphia—strongly informs its strategy for the Navy Yard, where the focus is on building a cohesive community that fosters employment, innovation, and production. PIDC manages all aspects of the property’s management and development, including master planning, leasing, property management, infrastructure development, utility operation, and structuring development transactions. www.PIDCphila.com | www.navyyard.org

About The Chamber of Commerce for Greater Philadelphia’s CEO Council for Growth

The Chamber of Commerce for Greater Philadelphia’s CEO Council for Growth (CEO Council) leads our region forward by envisioning a stronger, more competitive community, convening decision makers, taking action, and advocating for policies and practices that strengthen our regional economy. The CEO Council advocates through its members and engages stakeholders to enhance economic growth and prosperity in the region. We prioritize the revitalization and enhancement of our region’s talent, mobility, and innovation. The CEO Council’s Cell & Gene Therapy Initiative is leveraging Greater Philadelphia’s specialized assets to accelerate growth and promote the region as the global hub of research, talent, capital, and companies in cell & gene therapy, gene editing, and connected health. www.ceocouncilforgrowth.com

About Iovance Biotherapeutics

Iovance Biotherapeutics, Inc. aims to be the global leader in innovating, developing, and delivering tumor infiltrating lymphocyte (TIL) therapies for patients with cancer. We are pioneering a transformational approach to cure cancer by harnessing the human immune system’s ability to recognize and destroy diverse cancer cells in each patient. The Iovance TIL platform has demonstrated promising clinical data across multiple solid tumors. We are committed to continuous innovation in cell therapy, including gene-edited cell therapy, that may extend and improve life for patients with cancer. www.iovance.com

About Integral Molecular

Integral Molecular is the industry leader in creating and commercializing transformative technologies that advance the discovery of therapeutics against difficult protein targets. With 20+ years of experience focused on membrane proteins, viruses, and antibodies, Integral Molecular’s technologies have been integrated into the drug discovery pipelines of over 600 biotech and pharmaceutical companies to help discover new therapies for cancer, diabetes, autoimmune disorders, and viral threats such as SARS-CoV-2, Ebola, Zika, and dengue viruses. www.integralmolecular.com

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Wistar Melanoma Researchers Discuss Risks and Solutions for Melanoma Awareness Month

Three of The Wistar Institute’s foremost melanoma researchers: professor Meenhard Herlyn, D.V.M., D.Sc.; associate professor Jessie Villanueva, Ph.D.; and assistant professor Noam Auslander, Ph.D. discussed the progress and potential in melanoma research. Each brings their own distinct expertise to the field of melanoma research with decades of combined experience, and in reflecting on the state of the field, Drs. Herlyn, Villanueva, and Auslander covered both how they came to melanoma research and how they continue to tackle the challenge of this disease every single day at Wistar.

There are a lot of cancers out there. What brought you to melanoma?

Dr. Noam Auslander: As someone who works on the computational side of things, I was attracted to melanoma research mainly because of the quantity of data. In science generally but in computational science in particular, more data is better — because that allows researchers to design high-fidelity models, which, with cancer, can lead to all sorts of benefits, like predictions of who will respond to what therapy, or which genetic patterns are implicated in a cancer.

I can access and analyze melanoma data in large batches simply because there’s a lot of it. Part of that is because it’s a common cancer — which isn’t a good thing — but because it’s both common and a subject of study for more than 40 years, that allows my team and I to improve our models.

Dr. Jessie Villanueva: For me, melanoma research began as pure scientific interest. Melanoma is an aggressive cancer, and when I started as a postdoctoral fellow, there were no approved targeted therapies or immunotherapies; if chemotherapy, radiation, and surgery all failed, there really weren’t other options.

That problem attracted me to the field as a scientist who wants to solve problems, and shortly afterward, the professional interest became a personal one: a childhood friend whom I’d known since kindergarten was diagnosed with melanoma, and not long after that, so was my uncle. Unfortunately, my uncle passed away, but my friend survived, and that combination of loss and hope solidified melanoma as something I wanted to dedicate myself toward working against.

Dr. Meenhard Herlyn: My story is not so inspiring. I was young — so I suppose it was something like a hundred years ago — but my boss told me to help him with a melanoma project, and that was that. But I was very lucky, because that project involved a man named Wallace Clark: a great pathologist of the disease, whose research laid the foundation for much of what we know today about melanoma. Much of his work was characterizing these melanoma cells under a microscope — a necessary first step — and thinking of stories in his mind about how they might behave. Characterizing and theorizing. So as a young scientist, I thought to myself, “we must find a way to fill in these stories with real data.” And I’ve followed that ever since.

There are other skin cancers; melanoma is just a subtype. What makes it so dangerous?

J.V.: Melanoma comes from cells that originally have an innate level of pluripotency (the ability to transform into different cell types); they have remarkable migratory abilities; and they give rise to a diverse array of cell types throughout the body. When those cells become cancerous, they are highly plastic and skilled at adapting to their environment. This plasticity also allows melanoma to evade treatment and become drug-resistant. Drug resistance is a big problem in the field; often when using drugs targeting one pathway, the tumors find an alternative pathway to exploit.

By collectively studying all the inner workings of melanoma — like its genetics (the kind of mutations it collects), epigenetics (how genes are turned on or off), and signaling pathways (controlling processes like cell growth, proliferation, and survival) — we aim to develop strategies that prevent tumors from evading treatment. We’ve made great progress treating melanoma, but tumors still develop strategies to bypass therapies. This ongoing challenge drives our relentless search for innovative and effective solutions, fueled by the hope of achieving cures and improving the lives of melanoma patients.

N.A.: Melanoma is associated with an unusually high inter- and intra-tumor heterogeneity; the mutational profile is exceptionally complex between different melanoma cells and even within melanoma cells. That’s why large-scale data analysis of melanoma with computational models isn’t just important but necessary — patterns that can help us fight this cancer exist, but distinguishing between patterns and noise both within a tumor and between tumors requires the help of advanced computational techniques.

Meenhard has talked about how we need to listen to cells, and that’s how I try to help Meenhard & Jessie’s work: by fine-tuning computer systems to listen for signals amid the chaos in cancer.

M.H.: We also have to remember that the cells that become melanoma are highly mobile by their very nature. As Jessie said, melanocytes have a certain amount of innate plasticity, which contributes to the cancer’s aggression once a melanocyte goes from normal to cancerous.

But that wouldn’t necessarily be as big a problem if it weren’t for these cells’ motility. When you have aggressive cancer cells moving throughout the body, that creates a situation that lends itself to metastasis. A skin cancer that isn’t melanoma doesn’t present as much danger because it’s probably more localized; I’m not saying that’s not serious, but a non-metastatic tumor on the skin is a lot easier to treat — at the simplest level, you just cut it off. With melanoma, once that diagnosis comes, the clock is ticking to stop the cancer before the metastatic impulse gets out of control.

More people are getting melanoma, with U.S. incidence up by more than 50% since 1999. Why do you think that is, and how can people protect themselves?

J.V.: The short answer is that we don’t yet know for sure — there are several ongoing epidemiological studies which we expect will provide clear answers. Lifestyle is a big part of it. Outdoor activity can be healthy; however, being outdoors means more sun & UV exposure. Anecdotally, since the pandemic, we’ve noticed more people spending more time outdoors. And that’s a risk factor.

We’re seeing a sharp increase in melanoma for young people, particularly young women. Cancer tends to be correlated with age — the older we get, the higher the probability of having cancer — but melanoma is the most frequently developed cancer in people in their 20s and 30s.

M.H.: I agree that lifestyle is probably a big factor in the increase in cases. Everything from tanning beds to taking a vacation to lie on the beach is going to give UV rays more opportunity to cause damage that could lead to melanoma. Sunlight feels good to everyone, but unprotected exposure is harmful. People get addicted to damaging UV because our skin secretes endorphins when exposed to UV, and that’s more reason to be cautious.

It’s true that people with less melanin in their skin are more at risk — which is why, for example, more leisure travel from countries in the Global North to equatorial regions that get more sun probably causes more melanoma overall — but everyone has skin, which means anyone can get melanoma. And that’s why awareness of exposure risk is so important.

The Wistar Institute Awarded Second National Science Foundation Grant to Expand Award-winning STEM Training Program

PRESS RELEASE

PHILADELPHIA — (May 14, 2024) — The Wistar Institute was awarded a $649,971 grant from the National Science Foundation (NSF) to support the continued expansion of its award-winning Biomedical Technician Training (BTT) Pre-apprenticeship Program. The grant supports Wistar’s reach to community colleges in New Jersey and Delaware who may have limited or no access to hands-on laboratory training and internships. This marks the second NSF grant supporting the Program’s continued expansion.

“As the Greater Philadelphia Region’s life science sector continues to expand, there is greater demand for laboratory technicians in both academic and industry labs,” said Dario Altieri, M.D., president and CEO, director of the Ellen and Ronald Caplan Cancer Center, and the Robert and Penny Fox Distinguished Professor of The Wistar Institute. “This 25-year program has offered career pathways to a candidate pool that is eager to join the life science sector and gain access to both entry-level and long-term careers here in Philadelphia.”

Created in 2000, The Wistar Institute’s BTT Program was initially designed as a two-summer, hands-on, mentored technician training program that prepared community-college students for positions in academic and biomedical, biotechnology, and pharmaceutical laboratories. Originally limited to students from Community College of Philadelphia (CCP), in 2021, Wistar received its first National Science Foundation (NSF) Advanced Technological Education (ATE) grant, Expansion, Curriculum Evolution, and Enhancement during BioTechnician Training (ExCEEd BTT), allowing it to expand from a cohort of 12 students from CCP to a cohort of 20 students from CCP and four other regional community colleges.

The latest grant, Tri-State ExCEEd BTT, will enable Wistar to bring its BTT Program to additional community colleges in New Jersey and Delaware starting in Summer 2025 through Summer 2027. The grant will expand the applicant pool in the Greater Philadelphia Region by including three additional community college collaborators, for a total of eight community colleges covering at least 10 counties in three states for Wistar’s BTT Pre-apprenticeship Program.

In ExCEEd BTT, students engage in a paid, accelerated, one-summer pre-apprenticeship training that includes a hands-on laboratory orientation at Wistar and two full-time, mentored experiences in academic and industry labs. Program graduates are prepared for immediate employment as laboratory technicians and may also continue training through Wistar’s registered Fox Biomedical Research Technician (BRT) Apprenticeship.

The BTT Program and BRT Apprenticeship provide training and research experiences not typically available to associate degree students, a segment of the workforce that is indispensable to support the success of an ever-expanding life science sector. Tri-State ExCEEd BTT supports Wistar’s commitment to building a diverse and inclusive life science sector talent pool. With this support from the NSF Wistar can expand its programming base and continue to train a diverse and underrepresented student population with limited access to life science research.

“By exposing students to Wistar science, we’re giving them access to the latest research, so they are ideally positioned for future careers,” explained Dr. Kristy Shuda McGuire, Dean of Biomedical Studies at The Wistar Institute. “Our approach is to work closely with faculty at community colleges to develop a cohesive program that offers students the foundational knowledge and the hands-on training they need to be successful. Then they put their knowledge and skills to work with two lab experiences with academic or industry collaborators here in the region doing cutting-edge science.”

Tri-State ExCEEd BTT will also add cell and gene therapy components to the current curriculum, provide a blueprint for incorporating a biotechnician pre-apprenticeship program into various biotechnology and science curricula at community colleges, and serve as a model for regional program expansion. New employer collaborators in two neighboring states will be recruited, allowing the registration of the apprenticeship for use nationally.

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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.


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Revealing Biology’s Hidden Patterns: Wistar’s Dr. Noam Auslander on the Power and Potential of Machine Learning

Dr. Noam Auslander, Ph.D., is assistant professor of the Molecular and Cellular Oncogenesis Program at the Ellen and Ronald Caplan Cancer Center. She focuses on developing machine learning methods to understand the factors driving cancer development and to identify patterns that can improve cancer diagnosis and treatment.

“If you define your problem correctly, and you have enough data, you have the ability to learn something very complex that you cannot see with your eyes.”

How would you explain the difference between artificial intelligence and machine learning to somebody who is not a scientist?

Artificial intelligence is more general term. Any software that imitates the human learning system is artificial intelligence. If you build a robot, and that robot does nothing but respond to your requests, that’s artificial intelligence. Machine learning is a field of study contained within artificial intelligence that involves creating sets of algorithms that can be used to learn a particular task, independent of receiving instructions from humans.

As your field has advanced, how much of that advancement has been a matter of increased computing power versus improved methods?

It’s both of those things combined. Increased computing power has allowed algorithms created 15 or 20 years ago to suddenly become very efficient, very good. These older neural networks had architectures that consumed too much computing power at the time, but once we had the GPUs, they started to work much better. And then based on that there has been an explosion of new research. The algorithms have evolved even more, making them much, much better.

What role do you see for machine-learning models in biomedical data analysis and research?

Our models can extract more information and identify more patterns in data than humans could on their own. Right now, people are building models that will do things like predict clinical outcomes, predict biological factors, and understand more about biology. I think that’s very promising, because if you define your problem correctly, and you have enough data, you have the ability to learn something very complex that you cannot see with your eyes. But still, it requires a person who understands the data, understands what they are doing, and understands how to use the model correctly.

How do you develop models that can be used to generate meaningful insights about real-world data?

We first need to understand the question or problem we’re trying to address, and we need to understand the data well enough to represent it correctly in the algorithm. This usually means talking with the clinicians or the biologists to understand what they’re trying to do. We also need to understand how we define a good performance. Is the goal to build a test that can be used in the lab or in the clinic? Or are we trying to learn something new in biology? All of these factors go into designing the model.

What makes some data sets better suited to a machine learning approach than others?

In general, the more data we have, the more amenable it is for these methods, especially if it’s good, clean data. But there are also scenarios where you can take a model that’s been trained for one thing and apply it to another task. A good example is imaging data, like radiology. You can take a pre-trained model for imaging that has already looked at a lot of data. And instead of training the entire architecture, you can train a part of it to only recognize the specific thing you are trying to recognize. You’re using technology that has already learned from other problems that you had much more data for, and this makes it much, much easier.

What’s your biggest frustration you encounter when developing and training models?

It’s almost always not enough data. That can lead to overfitting, which means the model stays too close to the training data set and can’t begin to generalize and make the predictions that allow it to work independently. Or sometimes the data is too complex, we can’t trust it, it’s not annotated correctly, or there are clinical variables that are notated differently by different clinicians. Those kinds of things make it very difficult for us.

How do you keep up with all the changes in your field?

The area of machine learning is moving very fast, so we have to keep track of a lot of literature and a lot of new technology. It’s impossible to follow everything that happened even in the last year — if you’re two to five years behind, that’s pretty good. At the same time, it’s a very interdisciplinary field, so for every project we do, we have to keep up with the research in at least two different disciplines. So, in a way, we are keeping up with at least twice as much as what normal researchers do.

What do you think is the most fun or interesting thing about what you do?

It’s always fun and interesting to work in an area that’s changing so fast — you can be the first to do a lot of things. If you think of an important problem or question, you can be the person to address it. And because there is so much data being generated, we can make real biological discoveries, find out completely new things, without relying on a lab. We can use data that’s already out there and find out something that’s completely new.

The type of work you do requires a lot of creativity and problem solving. When you feel stuck on a problem, how do you get your creativity flowing again to look at the problem in a new way?

When I get stuck on a problem, like part of an algorithm not working, I leave it for a while. I’m a runner, so sometimes I’ll go for a run, and while I’m running I’ll have better ideas come to me. I think it’s always good to stop looking at the problem. Leave it for a while, then come back and take a fresh look.

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Wistar Scientists Discover New Immunosuppressive Mechanism in Brain Cancer

PRESS RELEASE
Wistar’s Veglia lab identified how glioblastoma evades the immune system by inducing pro-tumor macrophages via a glucose based epigenetic modification.

PHILADELPHIA — (May 3, 2024) — The Wistar Institute assistant professor Filippo Veglia, Ph.D., and team, have discovered a key mechanism of how glioblastoma — a serious and often fatal brain cancer — suppresses the immune system so that the tumor can grow unimpeded by the body’s defenses. The lab’s discovery was published in the paper, “Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma,” in the journal Immunity.

“Our study shows that the cellular mechanisms of cancer’s self-preservation, when sufficiently understood, can be used against the disease very effectively,” said Dr. Veglia. “I look forward to future research on metabolism-driven mechanisms of immunosuppression in glioblastoma, and I’m hopeful for all that we will continue to learn about how to best understand and fight this cancer.”

Until now, it has been poorly understood how monocyte-derived macrophages and microglia create an immunosuppressive tumor microenvironment in glioblastoma. The Veglia lab investigated the cellular “how” of glioblastoma immunosuppression and identified that, as glioblastoma progressed, monocyte-derived macrophages came to outnumber microglia — which indicated that monocyte-derived macrophages’ eventuality to becoming the majority in the tumor microenvironment was advantageous to the cancer’s goal of evading immune response. Indeed, monocyte-derived macrophages, but not microglia, blocked the activity of T cells (immune cells that destroy tumor cells), in preclinical models and patients. The team confirmed this finding when they assessed preclinical models of glioblastoma with artificially reduced numbers of monocyte-derived macrophages. And as the group expected, the models with fewer malicious macrophages in the tumor microenvironment showed improved outcomes relative to the standard glioblastoma models.

Glioblastoma accounts for slightly more than half of all malignancies that originate in the brain, and the prognosis for those diagnosed with the cancer is quite poor: only 25% of patients who receive a glioblastoma diagnosis will survive beyond a year. Glioblastoma is inherently dangerous due to its location in the brain and its immunosuppressive tumor microenvironment, which renders glioblastoma resistant to promising immunotherapies. By programming certain immune cells like macrophages, (such as monocyte-derived macrophages and microglia), to work for — rather than against — the tumor, glioblastoma fosters a tumor microenvironment for itself that enables the cancer to grow aggressively while evading anticancer immune responses.

Having confirmed the role of monocyte-derived macrophages, the Veglia lab then sought to understand just how the cancer-allied immune cells were working against the immune system. They sequenced the macrophages in question to see whether the cells had any aberrant gene expression patterns that could point to which gene(s) could be playing a role in immunosuppression, and they also investigated the metabolic patterns of macrophages to see whether the macrophages’ nonstandard gene expression could be tied to metabolism.

The team’s twin gene expression & metabolic analysis led them to glucose metabolism. Through a series of tests, the Veglia lab was able to determine that monocyte-derived macrophages with enhanced glucose metabolism and expressing GLUT1, a major transporter for glucose (a key metabolic compound), blocked T cells’ function by releasing interleukin-10 (IL-10). The team demonstrated that glioblastoma-perturbed glucose metabolism in these macrophages induced their immunosuppressive activity.

The team discovered the key to macrophages’ glucose-metabolism-driven immunosuppressive potency lies in a process called “histone lactylation.” Histones are structural proteins in the genome that play a key role in which genes — like IL-10 — are expressed in which contexts. As rapidly glucose-metabolizing cells, monocyte-derived macrophages produce lactate, a by-product of glucose metabolism. And histones can become “lactylated” (which is when lactate becomes incorporated into histones) in such a way that the histones’ organization further promotes the expression of IL-10 — which is effectively produced by monocyte-derived macrophages to help cancer cells to grow.

But how can the glucose-driven immunosuppressive activity of monocyte-derived macrophages be stopped? Dr. Veglia and his research team identified a possible solution: PERK, an enzyme they had identified as regulating glucose metabolism and GLUT1 expression in macrophages. In preclinical models of glioblastoma, targeting PERK impaired histone lactylation and immunosuppressive activity of macrophages, and in combination with immunotherapy blocked glioblastoma progression and induced long-lasting immunity that protected the brain from tumor re-growth — a sign that targeting PERK-histone lactylation axis may be a viable strategy for fighting this deadly brain cancer.

Note: The work detailed in this publication was initiated at The H. Lee Moffitt Cancer Center during Dr. Veglia’s time there and continued at Wistar.

Co-authors: Alessandra De Leo, Alessio Ugolini, Fabio Scirocchi, Delia Scocozza, Barbara Peixoto, Paulo C. Rodriguez, and Filippo Veglia of the Department of Immunology at the H. Lee Moffitt Cancer Center; James K. C. Liu, Arnold B. Etame, Michael A. Vogelbaum, and Filippo Veglia of the Department of Neuro-Oncology at the H. Lee Moffitt Cancer Center; Xiaoqing Yu of the Department of Biostatistics and Bioinformatics at the H. Lee Moffitt Cancer Center; Alessandra De Leo, Alessio Ugolini, Barbara Peixoto and Filippo Veglia of The Wistar Institute; Alessio Ugolini, Fabio Scirocchi, Angelica Pace, Aurelia Rughetti and Marianna Nuti of the Department of Experimental Medicine at Sapienza University of Rome; Luca D’Angelo and Antonio Santoro of the Department of Human Neurosciences at Sapienza University of Rome; and Jose R. Conejo-Garcia of Duke School of Medicine.

Work supported by: This work was supported by The Ben & Catherine Ivy Foundation Emerging Adult Glioma Award, The National Institute of Neurological Disorders and Stroke (1R01NS131912-01), by American Cancer Society Institutional Research Grant (IRG-21-145-25). It is supported in part by the Flow Cytometry Core Facility, the Molecular Genomics Core, Proteomics & Metabolomics Core Facility, Biostatistics and Bioinformatics Shared Resource at the H. Lee Moffitt Cancer Center & Research Institute, a Comprehensive Cancer Center designated by the National Cancer Institute and funded in part by Support Grant (P30-CA076292). Human specimen collection (Policlinico Umberto I) was in part supported by grant RM120172B803DB14.

Publication information: “Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma,” from Immunity.

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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.


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The Wistar Institute and Collaborators Celebrate Two New Cohorts of Philly’s Life Science Workforce

University City, Philadelphia may have been quieter than usual with so many taking spring breaks, but March was a busy month for The Wistar Institute’s Hubert J.P. Schoemaker Education and Training Center: not one but two cohorts of the Institute’s renowned Biomedical Technician Training (BTT) Program were celebrated at completion ceremonies.

The BTT Program, created in 2000 at Wistar by Dr. William Wunner, has grown from a two-summer program in collaboration with Community College of Philadelphia to a thriving scientific workforce development program that supports the region’s life science industry. Since its expansion — made possible by funding from the National Science Foundation, the Commonwealth of Pennsylvania Department of Labor & Industry PAsmart Program, Philadelphia Works, PIDC, GSK, and others — the BTT Program has become an opportunity for dynamic collaboration across a host of educational partners, workforce intermediaries, and life science companies.

After completing prerequisite classes to cover the foundations of cellular and molecular biology, BTT participants then complete an intensive, hands-on 2-week Orientation in Wistar’s Training Laboratory, followed by 10-12 weeks of on-the-job training in laboratories at The Wistar Institute and/or partner laboratories that have the option of hiring trainees upon completion. As trained and certified biomedical technicians, the programs’ participants are now prepared to pursue lasting and meaningful careers in the city’s booming life science industry.

The first cohort — a collaboration between The Wistar Institute, Iovance Biotherapeutics, West Philadelphia Skills Initiative, and the Greater Philadelphia Chamber of Commerce, with additional support from the Philadelphia Navy Yard Skills Initiative and PIDC made possible by Congresswoman Mary Gay Scanlon — was recognized on Friday, March 22nd at a ceremony in Iovance’s Cell Therapy Center at the Philadelphia Navy Yard. To mark the occasion of the Biomedical Technician Training Program: Aseptic Manufacturing Program certifying its second cohort of trainees in two years, Philadelphia Mayor Cherelle Parker attended to join the participants, families, and program sponsors in recognition of the continued success and promise that the program heralds in Philadelphia.

“I hope you feel special, because you’ve earned access to something that puts you in another space and place in our city,” said Mayor Parker, addressing the 12 Philadelphians assembled to receive their certificates of completion.

“You’re doing work that’s saving lives, transformative work. But you can’t just be successful. You’ve got to go back to the people that are like you who’ve never even thought about the industry, because they didn’t even know that it exists. You’ve got to say to them, ‘Do what I did — you can do what I did.’”

The second cohort — in collaboration with Children’s Hospital of Philadelphia (CHOP) and West Philadelphia Skills Initiative and supported by Philadelphia Works and Citizens Bank — celebrated their completion on Monday, March 25th, at CHOP’s Roberts Center for Pediatric Research, where nine trainees were awarded certificates in a ceremony attended by families, CHOP lab members, and representatives of the organizations who made the program possible.

Wistar’s dean of Biomedical Studies, Dr. Kristy Shuda McGuire, spoke to the success of the trainees and the program, which lay in the combination of programmatic excellence and can-do spirit of all involved, from students to staff.

“If we are to teach students science, then we need students to do science,” said Dr. Shuda McGuire, emphasizing the importance of hands-on, continuous learning as the backbone of the scientific professions. “You all have great things ahead of you.”

The trainees agreed. The designated student speaker, Michael Nguyen, described the transformative impact that the BTT Program had on him.

“Almost a year ago today, I was working a manual labor job that was all pain, with no direction or purpose in life. I was living paycheck to paycheck, day to day,” said Nguyen.

“But today, I can say that going through this program with the people involved in it changed my life. It taught me not just science, but how to get myself out there, gain skills, network — and most importantly, to believe in myself and realize that I can do anything with hard work and dedication.”

With his certificate in hand and enthusiasm for science only growing, Nguyen hopes to return to school to “put some more letters at the end of my name” and continue working in research.

The ceremonies may have ended, but the Philadelphia life science workforce can count itself all the stronger for not one but two newly trained cohorts of biomedical technicians who have the opportunity to use their skills to share in the progress and prosperity of the Philadelphia life science economy. In the words of one student: “I see myself here for the long run.”

Promising Personalized Approach to Liver Cancer Therapy Made Possible by DNA-based Neoantigen Research Designed at The Wistar Institute

PRESS RELEASE
Geneos Therapeutics, Wistar, and Collaborators Translate Personalized DNA Vaccine Technology into Clinical Outcome Based on Mistakes Tumors Make

PHILADELPHIA — (Tuesday, April 30, 2024) — Hepatocellular carcinoma (HCC), or liver cancer, is an aggressive malignancy with limited treatment options. An immunologically cold cancer — meaning the tumors can effectively hide themselves from the immune system — liver cancer can escape or not respond to first-line treatment options, resulting in a poor prognosis. The results of a new clinical trial published in Nature Medicine show that a novel, personalized neoantigen vaccine therapy demonstrated promising anti-tumor efficacy in patients with liver cancer who failed their original front-line treatment. The foundational biomedical research leading to this important study and important outcome originated from research in the Vaccine & Immunotherapy Center at The Wistar Institute.

The clinical trial was directed by the Philadelphia biotherapeutics company, Geneos Therapeutics — along with a scientific team of collaborators including The Wistar Institute — in the paper, “Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial.”

Of the 36 participants enrolled, 34 were evaluable (i.e., able to be studied under the trial guidelines) among these, eleven demonstrated tumor regression by clinically defined Response Evaluation Criteria in Solid Tumors (RECIST), resulting in a tumor regression rate of 30.6% — supporting a response to their therapy. Of those eleven, eight had partial vaccine responses (meaning their tumors decreased in size, with one such patient’s tumor shrinking enough to be surgically removed), and three had complete responses — meaning their observable tumors were eliminated. An additional 9 patients exhibited stable disease under treatment. While not a direct clinical endpoint, these patients’ disease appeared to stop progressing. The range for the median survival in months for patients with liver cancer who have failed first-line therapy is described as 12.9-15.1 months; however, the median overall survival at the time of the study’s data cutoff was 19.9 months, with 17 of the participants still being monitored for overall survival at the time of publishing.

In context, the results support a significant increase in survivorship for patients with this notoriously aggressive & difficult-to-treat cancer compared to historical endpoints. Though Phase 1/2 safety and efficacy studies are an important initial step in clinical advancement of a new therapeutic, these notably positive results open the possibility for additional research to be conducted to evaluate the use of the team’s neoantigen vaccine in expanded HCC cancer studies as well as to extend this technology to additional cancers.

The host immune system has powerful immune surveillance effectors termed “Killer T cells,” or CTLs, which serve to eradicate foreign elements such as viruses growing in host cells by killing the entire cellular factory. However, the ability to recognize tumor antigens that are hiding in host cells is a much more difficult task. Accordingly, as cancers grow, they can overwhelm the host through increasingly rapid cell division, but they also incorporate mutations or “mistakes” in multiple of the cancer cells’ protein sequences, in part due to their bypassing normal cell stringent regulatory processes. Those mutations occurring in tumors’ proteins are termed neoantigens (NeoAg): proteins that are expressed uniquely in cancers as a by-product of cellular dysfunction.

Geneos scientists worked with scientists in The Wistar Institute Vaccine & Immunotherapy Center — led by David B. Weiner, Ph.D., Wistar Executive Vice President, Vaccine & Immunotherapy director, and W.W. Smith Charitable Trust Distinguished Professor in Cancer Research — to conceptualize and optimize a unique gene assembly process to create highly consistent and effective NeoAg building blocks driving effector T cells consistently in vivo.

As a model for designing human NeoAg vaccine cassettes, the scientists first sequenced mouse tumor DNA and RNA and used defined AI-based approaches to identify the collection of “mistakes” that were most immune activating in any particular tumor. Assembly and clipping of each specific tumor mistake were assembled into a sequence of immune strings that used DNA intervening sequences to physically “separate” each individual NeoAg in the string. Next, the string’s ability to drive was evaluated to ensure that the placement of a particular neoantigen along the string was capable of retaining its immune potency. They documented that the final cassette strings as DNA vaccines induced potent induction of T cell immunity and could regress and clear tumors in preclinical model studies. Without the NeoAg vaccination, the control models’ immune systems ignored tumors when challenged which grew unabated in these animals. They then studied sequences derived from human tumors as well to further advance this research towards the clinic.

While neoantigens produced by liver cancer don’t typically trigger strong immune responses, the team hypothesized that their improved neoantigen vaccine strings as well as the inclusion of immune-stimulating signals that the lab had developed could train the immune system to better recognize and eradicate the malignancy.

Accomplishments in the lab validated the utility of assembling specifically designed larger collections of NeoAgs in a single vaccine (40Ags), including specific processing signals to preserve the integrity of each potential NeoAg in the string. The team’s technology was also able to include specific T cell expansion signals associated with activation of CD4 and CD8 Killer T cell immunity built into the vaccines’ DNA designs, among other innovations; these design elements showed that the technologies were well tolerated and could protect preclinical models from cancer challenge.

“We’re very pleased to have played a role, working together with Geneos and the entire team in advancing this important, exciting technology and to see its impact in patients in the important GT30 clinical trial,” said David B. Weiner, Ph.D. “Advancing the next generation of nucleic acid immune weapons for impacting intractable cancers is a major focus of our team.”

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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.


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