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Tag: Ertl

Wistar Scientists Enhance Cell-Based Therapy to Destroy Solid Tumors

PHILADELPHIA—(Dec. 13, 2023)—Wistar researchers successfully tested a simple intervention that could unlock greater anti-tumor power in therapies that use T cells — an approach known as “cell-based therapy,” which uses specially designed T cells to fight cancer. Led by Dr. Hildegund C.J. Ertl — a professor in The Wistar Institute’s Vaccine & Immunotherapy Center — the team has proven an exciting concept: that the common cholesterol drug fenofibrate can boost T cells’ ability to destroy human tumors, as described in their new paper, “Treatment with the PPARα agonist fenofibrate improves the efficacy of CD8+ T cell therapy for melanoma,” published in Molecular Therapy Oncolytics.

CD8+ T cells work very well in fighting liquid tumors, but for solid tumors like melanoma, the cell-based therapy approach can stall due to the physical structure of the cancer. The T cells infiltrate the tumor, but the cancer adapts and saps the T cells’ energy by hijacking the form of metabolism that the T cells use: glycolysis, which turns sugar into energy. Without energy, the T cells first lose functions and then die, and the cancer continues to grow.

But Dr. Ertl’s team has been able to circumvent this problem by forcing T cells to use a different energy source than glucose. They used fenofibrate because, as a cholesterol-lowering compound, the drug is a PPARα agonist. When PPARα is upregulated, cellular metabolism is switched from glycolysis to fatty acid oxidation, or FAO. This mechanism works to improve cholesterol levels in human patients, but for Dr. Ertl’s purposes, the fenofibrate-induced switch to FAO provided T cells with a form of energy that cancer couldn’t exploit — which is how Dr. Ertl proved that fenofibrate has been able to boost the killing power of T cells deployed against cancerous cell lines.

In this paper, the authors wanted to see whether this kind of cancer-killing improvement would have similar effects when deployed against not just cancer cell lines but solid human tumor fragments — a more challenging proposition. The group treated T cells with fenofibrate, and the hypothesis held: Dr. Ertl’s team watched the T cells treated with fenofibrate survive longer and kill more cancer in preclinical models with human solid tumor masses than the T cells that didn’t receive the treatment.

“Treating T cells with fenofibrate before using them as a cancer treatment flips a switch of sorts in their metabolism,” said Dr. Hildegund Ertl. “Once that switch is flipped, T cells can destroy the cancer much more effectively. And we’ve confirmed that this holds for larger human tumor masses.”

As a result of these findings, Dr. Ertl and her team think this intervention shows great promise for future anti-tumor therapies. “Melanoma is the most dangerous form of skin cancer. Anything we can do to chip away at the cancer and destroy more of it — even a simple pre-treatment step like this one — can make a world of difference.”

Co-authors: Mohadeseh Hasanpourghadi, Arezki Chekaoui, Sophia Kurian, Robert Amrose, Wynetta Giles-Davis, Amara Saha, and Hildegund C.J. Ertl of The Wistar Institute; Raj Kurupati of The Wistar Institute and The Janssen Pharmaceutical Companies of Johnson & Johnson; and Xu Xiaowei of the Hospital of the University of Pennsylvania

Work supported by: Department of Defense grant number W81XWH-19-1-0485 CA180191.

Publication information:Treatment with the PPARα agonist fenofibrate improves the efficacy of CD8+ T cell therapy for melanoma,” published in Molecular Therapy Oncolytics.

Dr. Hildegund Ertl: Vaccine Thought Leader and Formidable Presence

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Philanthropy Powering Science: $1.6M in New Funding for Wistar Coronavirus Research

In mere weeks, philanthropic support of Wistar’s Coronavirus Discovery Fund has exceeded $1.6M in new funding thanks to an extraordinary response from individuals, foundations, and corporate sponsors. As our scientists focused their research to advance vaccines, drugs, and diagnostics targeting the novel coronavirus, SARS-CoV-2, Wistar donors moved with the same speed, committing to put our discovery science into action in a variety of important ways. This pace of investment in research now underway at Wistar will allow us to accelerate and potentiate progress against SARS-CoV-2 and future viral threats the world may confront.

Under the leadership of Dr. David Weiner, executive vice president, director of the Vaccine & Immunotherapy Center (VIC), and W.W. Smith Charitable Trust Professor in Cancer Research, our team continues to carry out pivotal laboratory testing of its synthetic DNA vaccine. Funding support has enabled us to expand that research through the purchase of critical equipment that allows for real-time, high-throughput assays required for vaccine development, and will hasten the Institute’s ability to respond to future pandemic threats as they arise.

Dr. Daniel Kulp, associate professor in the VIC, is engineering nanoparticle-based immunotherapies that target SARs-CoV-2. He and his team use extremely small (nano) particles to display multiple copies of critical parts of the virus in order to stimulate immunity against COVID-19.  Donor support for his project is allowing the lab to design molecular simulations of the SARS-CoV-2 spike protein — the surface protein that lets the virus invade healthy cells.

Not only did individual donors make a strong commitment to Wistar Science; so did foundations, including The G. Harold and Leila Y. Mathers Charitable Foundation. Dr. Hildegund Ertl, vaccine expert and a professor in the VIC, is creating a SARS-CoV-2 vaccine based on safe viral delivery technologies. Genetically modified adenoviruses are great delivery vehicles for vaccines because they induce neutralizing antibodies and killer T-cell responses. Dr. Ertl’s goal is to apply innovative technologies created in her lab to develop a vaccine that will produce strong and sustained protection to COVID-19. The Mathers Foundation and steadfast Wistar supporters quickly mobilized to provide critical support for this project.

This is not Wistar’s first pandemic. We are uniquely prepared for this moment by a near-century’s worth of Wistar achievement in developing vaccines that have saved countless lives. Wistar’s community of supporters has provided the resources and tools our scientists need to work efficiently and effectively to address this pandemic. For that, we thank you deeply. We’re all in this for science. Because Wistar Science saves lives.

If you would like to play a role in advancing Wistar’s research fighting COVID-19, your donation will keep the momentum going and inspire our scientists to continue tackling the world’s biggest threats. 

Spotlight on Wistar COVID-19 Researcher: Hildegund C.J. Ertl, M.D. 

Dr. Ertl is a global leader in Wistar’s Vaccine & Immunotherapy Center whose research focuses on preventing rabies, HBV, HIV, HPV, influenza, and other deadly viruses using innovative patented technologies. In response to the global COVID-19 emergency, the Ertl lab quickly applied some of these technologies to the development of a vaccine. She illustrates her approach and its advantages below.

Despite a record amount of research efforts on the novel coronavirus that is plaguing the globe, there is still a lot we don’t know, especially regarding the immune response that we develop against it. Therefore, in my lab we are taking a multi-pronged approach to maximize our chances of success.

The coronavirus is known for its unique crown-like shape, given by the “spikes” that cover the outside of the virus. These spikes act like “keys” that insert themselves into a “lock”, known as a receptor on the host cell, which then opens the door to host cell infection. Many researchers have chosen the spike as their vaccine target to prevent COVID-19 because antibodies that can block this key from accessing its lock should protect the host cells from infection. However, studies on other coronaviruses have shown that antibodies may not provide long-term and durable protection, so my lab is taking a dual-pronged approach to mobilize defenders within the immune system.

We have designed a vaccine strategy that targets both the spike and another protein on the viral coat using a proprietary platform developed in our lab to enhance immune response to the vaccine, which has shown promising effects in several settings.

To be more specific, we genetically modify adenoviruses to act as vaccine delivery vehicles because of their ability to stimulate potent and durable immune responses. Adenoviruses, which naturally cause mild or non-symptomatic respiratory illnesses, can be made incapable of replicating and causing infection and used as a platform for vaccine development.

This technology is very effective, relatively inexpensive and safe. Although no human vaccines based on replication-defective adenovirus vectors are currently on the market, several have been extensively tested in clinical trials.

One consideration that needs to be accounted for when working with human adenoviruses is that they are very prevalent in the population and most people are naturally exposed to them in early childhood, so that most adults carry in their blood antibodies that can inactivate adenovirus-based vaccines and reduce their efficacy.

To circumvent the issue of pre-existing immunity, my lab has pioneered the use of a weakened version of an adenovirus that causes infections in animals and has been modified so that it can’t grow in humans. We have used this approach for rabies and HIV vaccines that have shown efficacy in preclinical models.

We are quickly adapting this platform for COVID-19 vaccine development. Another group that I have collaborated with for many years at the University of Oxford is developing an adenovirus-based vaccine that has entered clinical trial stage a few weeks ago, but our approach provides further advantages because, as explained above, it targets two viral proteins and has the ability to further boost the immune response.

I am hopeful that our strategy can be successful because I believe that, at the moment, adenovirus-based vaccines are one of our best shots.

Dr. Ertl’s COVID-19 vaccine research has received critical support from the The G. Harold and Leila Y. Mathers Charitable Foundation, thanks to which she is able to bring her deep knowledge and expertise to the vaccine race to curb the pandemic. Dr. Ertl and Wistar are very grateful to Mathers for stepping in and providing much needed funding to move this research forward as fast as possible and for its continuous support of Wistar science. Dr. Ertl is also the co-founder of Virion Therapeutics, LLC, a Philadelphia-based start-up spun out of The Wistar Institute, developing new vaccine platform technologies.

Virion Therapeutics, LLC Raises $5 Million to Develop Checkpoint Inhibitor Powered Vaccine Therapies for Treatment of Virally Induced Infectious Diseases & Cancers

PHILADELPHIA — (Sept. 26, 2018) — A new Philadelphia-based start-up, Virion Therapeutics, LLC spun out of The Wistar Institute, will work to advance innovative, immune-based therapies for the treatment of chronic viral-associated cancers and viral infections utilizing the first genetically encoded checkpoint inhibitor that can be given via vaccination. Virion is co-founded by Hildegund C.J. Ertl, M.D., professor in the Vaccine & Immunotherapy Center at Wistar, along with life science entrepreneurs Andrew D. Luber, Pharm.D., and Bernard Rudnick, MBA.

The Virion technology is built on a two-prong strategy that combines the use of replication-incompetent chimpanzee adenoviral vectors (ChiVax) with concomitant expression of glycoprotein D (gD), a novel checkpoint inhibitor that blocks suppression of T-cell production. ChiVax vaccines overcome a key limitation of human adenovirus-based vaccines, whose efficacy can be limited by pre-existing natural immunity against human adenoviruses. Incorporating gD as a BTLA checkpoint blockade into multiple vaccine platforms has consistently shown enhanced T-cell responses. When combined in a single vaccine, ChiVax-gD induces potent, durable and wide-ranging T-cell responses that are more resistant to immune exhaustion and has shown enhanced activity in multiple preclinical cancer and infectious diseases studies.

“We are very excited to be able to move our promising vaccine work to clinical development,” said Ertl. “Our vaccine platform has undergone extensive characterization and pre-clinical testing and is ready for translation into clinical trials to help cure common and devastating diseases, including chronic hepatitis B virus (HBV) infection and cancers caused by human papillomavirus (HPV) infection which include cervical, anal, penile, and head and neck cancers.”

“Immunotherapy is a very dynamic area of treatment with first generation checkpoint inhibitor therapies showing great promise,” said Rudnick, Virion’s chief executive officer. “Our technologies provide an innovative solution for many limitations of these first generation agents, thereby offering potential treatment options for patients living with certain cancers or infectious diseases. Virion brings together a world-class team of experienced biotechnology and pharmaceutical experts to help commercialize this excellent science from Wistar, so we are well equipped to bring novel immune-based treatments to this rapidly expanding market.”

Since its launch in early 2018, Virion has received more than $5 million in Series A funding from U.S. and international Angel investors and family offices that have included Robin Hood Ventures, Mid-Atlantic Bio Angels Group (MABA), Keiretsu Capital Fund III, Life Science Angels, Keiretsu Forum, Alliance of Angels, and Crimson Peak. The capital will back Virion’s efforts for an FDA Investigational New Drug filing for its lead HPV vaccine candidate and pre-clinical work on a vaccine for chronic HBV infection.


The Wistar Institute
The Wistar Institute is an international leader in biomedical research with special expertise in cancer and infectious disease research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. Wistar’s business development team is advancing Wistar science and technology development through creative partnerships. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible.

Virion Therapeutics, LLC.
Virion Therapeutics, LLC, is a science driven company developing innovative immune-based treatments for virally associated cancers and chronic viral infections utilizing the first genetic construct checkpoint inhibitor given via vaccination. Our vaccines represent novel and highly effective platforms to induce potent and sustained T cell-mediated immune responses, allowing us to target common diseases with unmet medical needs. Founded in early 2018 to advance technology licensed from The Wistar Institute, a global leader in vaccine science, Virion has built an experienced biotechnology management team, augmented by its advisory board that has extensive domain knowledge in antiviral, vaccine and oncology therapeutic arenas.