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Wistar Scientists Develop Novel Antibody Treatment for Kidney Cancer

Written by The Wistar Institute on . Posted in Press Releases.

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

Written by The Wistar Institute on . Posted in Press Releases.

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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Teaching Students How to Create Vaccines: Inside Dr. David Weiner’s Vaccines and Immune Therapeutics Class

Written by The Wistar Institute on . Posted in Featured News.

Since 1997, Wistar’s Dr. David Weiner has taught Vaccines and Immune Therapeutics for the University of Pennsylvania’s Perelman School of Medicine. After joining The Wistar Institute — where he serves as the Executive Vice President, W.W. Smith Charitable Trust Distinguished Professor in Cancer Research, and Director of the Vaccine & Immunotherapy Center — Dr. Weiner continued leading the class, which features world-class experts from an eminent roster of the best in vaccinology. Dr. Weiner’s 13-week fall-semester course is noted for its pragmatic approach to the science & process of vaccine design, with students hearing from the field’s most trusted experts.

Where did the idea to start this course come from?

Starting the course was a group effort: Paul Offit1, Stanley Plotkin2, Maurice Hilleman3, and myself. Then Emilio Emini4 and Kathrin Jansen5 joined shortly after, right at the beginning; point is, we had very big names.

There was a prevailing mood in the late 80s and early 90s that infectious disease had basically been conquered. Now, take a look around you: that’s obviously not true. But that was in the air at the time, and there weren’t any courses focusing on vaccines as such; all the immunology lectures tended to focus on the immunology theory, and if they wanted to get into the nitty-gritty, they’d talk about how mice respond to vaccines. But not how human immune systems respond to vaccines, which is what’s important for stopping infection in the real world.

At the time, my career had turned from cancer immunotherapy to vaccine technology. As a faculty member, I was building a new program in DNA vaccines, and I was working with all these vaccine people. We realized we had this gap in how we were teaching the students, so we started a course dedicated to how vaccines are actually made: how you design them, how you test them, how humans respond to them, and so on. And it isn’t just the science, although that’s the biggest part. Students learn that designing a vaccine in the lab is one thing, but it’s almost another challenge entirely to put shots in people’s arms — how scientists need to prepare for regulatory and market forces when designing vaccines.

What do the students learn?

Students who enroll should have background on the fundamentals of immunology, so that gives us the opportunity to get into the weeds on vaccine topics. That could be anything from how adjuvants are used in vaccines — which, by the way, are essentially immune irritants that you can put in a vaccine to make it more effective — to the procedural steps involved in actually getting a vaccine to market.

But I think that what’s really made this class special and such a hit for more than two decades is the caliber of the lecturers. We have a Who’s Who in vaccinology talking with our students. They get to learn from Kathrin Jansen, for example — who led the development of Gardasil, the first HPV vaccine — or, before he passed away, Maurice Hilleman, who I think has probably saved more lives than anybody else in history through his work at Merck. Students saw successes and failures throughout the years, like when the license for the rotavirus vaccine was announced or when the clinical trial for one of the first HIV vaccines failed; if you’re enrolled in this course, you’re up close and personal with the field in a way that, unless you already work in it, is unparalleled.

Students applaud Dr. Drew Weissman at Wistar for winning the 2023 Nobel Prize in Physiology or Medicine two days prior.

One thing I remind the students of, too, is that their access to the folks we have lecturing is an almost untold privilege; even working scientists may not ever speak with these superstars. Let me put it this way: you’re not talking to Emilio Emini unless you’re from someplace like CNN. And even then, it’s a question of whether he has time to step away from his work with Bill Gates. So when you ask why the course is so popular, I have to point to whom we’ve been able to recruit; our students learn from the best of the best.

If this course were taught in, say, the ‘60s, how would the lectures be different? How has the field evolved?

I think one of the great things about this course in particular is that it really captures the constant shift of technology. Even in the 90s, we were still mostly talking about live attenuated vaccines — the fundamental idea that a weakened pathogen can teach the immune system how to fight the real thing.

There’s nothing wrong with live attenuated vaccines; we don’t see polio anymore thanks to live attenuated vaccine design. But the field has grown so much since then, and our students get to see those advances almost in real time. Sea changes and shifts happen pretty frequently in vaccinology. We’ve seen the rise of adjuvants as vaccine enhancers; there’s been the development of DNA vectors, like the kind my lab works on; and then, of course, you have the mRNA revolution, which happened right before the students’ eyes when the COVID mRNA vaccines were developed at a record pace. Just this year, Drew Weissman6 wins the Nobel Prize on a Monday, and he’s here at Wistar teaching the class that Wednesday — where else do you have that?

This course was only started in ‘97, so I don’t think that any of our students have vaccines to their names yet. But the students who take this course frequently get jobs in academia or industry, and they’re well-prepared because they had the tremendous opportunity to hear first-hand from the most trusted experts in the field.

In terms of total lives saved, I don’t think any technology competes with vaccination. It’s our number one tool for fighting deaths caused by viruses. Making sure that our students can learn from the best and brightest in vaccinology paves the way for a new generation of experts — and many more millions of deaths prevented.

  1. Paul Offit, M.D., Maurice R. Hilleman Chair of Vaccinology at the Perelman School of Medicine ↩︎
  2. Stanley Plotkin, M.D., Professor Emeritus, The Wistar Institute ↩︎
  3. Maurice A. Hilleman, M.D., former Senior Vice President of Merck Research Labs ↩︎
  4. Emilio Emini, Ph.D., CEO of The Bill and Melinda Gates Medical Research Institute ↩︎
  5. Kathrin Jensen, Ph.D., former Head of Vaccine Research and Development at Pfizer ↩︎
  6. Drew Weissman, M.D., Ph.D., Roberts Family Professor in Vaccine Research at the Perelman School of Medicine and 2023 Nobel Laureate ↩︎

Wistar Scientists Engineer New NK cell Engaging Immunotherapy Approaches to Target and potentially Treat recalcitrant Ovarian Cancer

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA—(Nov. 1, 2023)— The Wistar Institute’s David B. Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center (VIC) and W.W. Smith Charitable Trust Distinguished Professor in Cancer Research, and collaborators, have engineered novel monoclonal antibodies that engage Natural Killer cells through a unique surface receptor that activates the immune system to fight against cancer.

In their publication titled, “Siglec-7 glyco-immune binding MAbs or NK cell engager biologics induce potent anti-tumor immunity against ovarian cancers,” published in Science Advances, the team demonstrates the preclinical feasibility of utilizing these new cancer immunotherapeutic approaches against diverse ovarian cancer types, including treatment-resistant and refractory ovarian cancers — alone or in combination with checkpoint inhibitor treatment.

The research started as a collaboration between Wistar’s Drs. Weiner and Mohamed Abdel-Mohsen, who were exploring the development of new glyco-signaling biologic tools that may be important in the fight against cancer.

Ovarian cancer (OC) is frequently diagnosed late in the disease process, and OC resistance to currently available treatments make it especially problematic; according to the NIH, the chances of someone diagnosed with OC and surviving for five years is around fifty-fifty. Ovarian cancer demonstrates a low response rate to standard-of-care treatments like chemotherapies, PARP inhibitors and the widely used checkpoint inhibitor, PD-1.

In the small proportion of ovarian cancer patients that do respond to these treatments, resistance becomes problematic over time — resulting in tumor escape and cancer progression. Genetic mutations, such as the well-known BRCA gene mutations, predispose women to a high risk of progressive OC. The CDC expects more than thirteen thousand women to die of ovarian cancer this year in the U.S. alone.

To combat ovarian cancer treatment resistance, the team hypothesized that they might be able to engage not only the traditional T cell immune arm of the immune system which PD-1 and known checkpoint inhibitors (CPI) activate, but also implement a strategy to activate Natural killer cells (NK cells), a subset of important anti-tumor immune cells, through a conserved glyco-immune marker found on the surface of most NK cells called Siglec-7 (Sialic acid-binding immunoglobulin-type lectin). NK cells have been recently described to express Siglec-7, so the team tested two new strategies to engage and activate NK cells against ovarian cancer through Siglec-7.

The first approach used human monoclonal antibodies (mAb) discovered and developed at Wistar and novel assays to visualize and demonstrate that certain anti-Siglec-7 mAbs could activate human NK cells — which, in the presence of the antibodies, responded against multiple human OC cell lines. These now-activated NK cells would kill OC but not non-cancer cells with the Siglec-7 mAb treatment.

The researchers demonstrated that multiple OC carrying mutations, including BRCA1 and BRCA2, could be targeted by Siglec-7 antibodies through activated NK cells. The group moved to study the treatment of OC in a humanized mouse model and observed that the Siglec-7 treatment could impact OC growth slowing the tumors and increasing the animals’ survival.

Having demonstrated the feasibility of utilizing a Siglec-7 mAb in OC models, the team thought there were additional ways to use the Siglec-7 mAb to further focus on OC disease. They hypothesized that directly fusing the Siglec-7 reactive binding site of the Siglec-7 mAb to a second mAb that uniquely binds late OC through a molecule named Follicle Stimulating Hormone receptor (FSHR), which they had previously developed, would create a targeted Siglec-7 bispecific antibody that could bind through two distinct targets creating a new class of NK cell engagers (NKCE).

The team sought to test whether this Siglec-7 NKCE approach would be effective through the direct linkage of potentially killer NK cells to a guided missile aimed specifically at OC, which would open up a new path to develop additional Siglec-7 based immunotherapeutic approaches. In both bench and humanized mouse challenge studies, the Siglec-7-NKCE was effective at targeting OC, activating NK cells in local proximity and efficiently killing multiple OC.

Both Siglec-7 technologies (mAbs and NKCEs) demonstrated an ability to recruit and activate the NK cell population, shrink tumors and prolong survival in the models studied. The observation of on-target specificity of the approaches suggests that cancer’s apparent Siglec vulnerability can be exploited therapeutically, perhaps with limited toxicity — a promising sign for the future of anti-cancer Siglec research, but the team cautions that more work in this regard is important.

In an additional set of preliminary studies, the team also found that this Siglec-7 approach could complement PD-1 checkpoint inhibitor (CPI) therapy. This is an important area of further study that could uncover more details of the mechanisms involved and possibly extend the utility of such CPI in OC and, potentially, other cancers. “These findings open the door to further exploration of how we can engineer Siglec-7 immunotherapies and perhaps other related molecules for ovarian cancer and perhaps a larger group of recalcitrant cancers,” stated Dr. David B. Weiner, adding, “Further studies may bring such approaches as described to represent new tools in our antitumor toolbelt.”

As always, more research is needed to refine these technologies further on the long journey from the lab bench to the clinic. But this paper offers a different avenue for attempting to exploit these unique interactions of immune surface molecules such as Siglec-7 and perhaps other Siglecs.

“We have observed not one but two methods that can target NK cells in an effort to control ovarian cancer in both Petri dishes and in vivo models,” said Dr. Devivasha Bordoloi, the first author on the paper. “This research shows a lot of promise, and I’m excited to move these studies to the next steps.”

Co-authors: Devivasha Bordoloi, Abhijeet J. Kulkarni, Opeyemi S. Adeniji, Pratik S. Bhojnagarwala, Shushu Zhao, Candice Ionescu, Alfredo Perales-Puchalt, Elizabeth M Parzych, Xizhou Zhu, Ali R. Ali, Joel Cassel, Rugang Zhang, Mohamed Abdel-Mohsen and David B. Weiner of The Wistar Institute; and M. Betina Pampena and Michael R. Betts of Perelman School of Medicine, University of Pennsylvania,

Work supported by: Department of Defense Ovarian Cancer Research Program award W81XWH-19-1-0189; the W.W. Smith Charitable Trust Professorship in Cancer Research; and the Wistar Science Accelerator Postdoctoral Fellowship.

Publication information: “Siglec-7 glyco-immune binding MAbs or NK cell engager biologics induce potent anti-tumor immunity against ovarian cancers,” from Science Advances.

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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 field 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.org.

Wistar Scientists Successfully Engineer a Goldilocks Construct: Therapeutic Antibody Could Be a Future Medicine to Improve Outcomes for Melanoma

Written by The Wistar Institute on . Posted in Featured News.

In recent years, multimodal therapies have emerged as a route to treat cancer by delivering different types of treatments together to improve effectiveness. However, the more modalities there are, the more complex the production and effects of these lifesaving treatments can become.

Wistar researchers have engineered a linked molecule that enables a three-modality therapy for treating melanoma. They accomplished this by connecting a cytokine and an antibody—which would ordinarily be administered separately—and then engineering a form that was pro-inflammatory enough to fight the cancer cells but not so inflammatory as to cause complications or reduce survival outcomes, according to a recently published study in Frontiers in Immunology.

“We took aspects of a cancer treatment regimen and tried to simplify that by combining antibody and cytokine together,” said Nicholas Tursi, the lead author on the study and a graduate student researcher in the lab of Dr. David Weiner, executive vice president, director of the Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Distinguished Professor at The Wistar Institute. “I focused on engineering an intermediate cytokine that is efficacious but also has an acceptable pro-inflammatory profile—a Goldilocks approach.”

The engineered “Goldilocks” cytokine Tursi and his colleagues, including Dr. Weiner and Dr. Daniel Kulp, Associate professor in Wistar’s Vaccine & Immunotherapy Center, engineered to test their antibody cytokine chimera was called HL2-KOA1, a modified designer version of the T cell growth factor IL-2. This engineered molecule used in a combination therapeutic regimen was effective at promoting survival in a rigorous melanoma model.

“What this suggests is that we could use other antibodies or cytokines to engineer the immune response to further extend efficacy,” said Tursi. He is hopeful that this research will serve as the foundation for developing other antibody cytokine chimeras that work for melanoma and potentially other cancers.

Up in (Antibody) Arms: Synthetic DNA Immunotherapy Platform Combats Brain Cancer

Written by The Wistar Institute on . Posted in Featured News.

Researchers in the Weiner Lab developed DNA-launched bispecific T cell engagers that controlled tumor growth and improved survival in glioblastoma.

Glioblastoma is one of the most severe and aggressive forms of brain cancer with limited treatment options and low survival rates. Wistar’s Weiner Lab is focused on creating new treatments to improve the patient’s quality of life and increase the opportunity to beat this difficult-to-treat cancer.

What approach is Dr. Weiner and his research team taking to tackle glioblastoma?

Dr. Weiner and his team are focused on dBTE’s – a synthetic DNA antibody platform for developing new T cell-redirecting immunotherapies. These immunotherapies deliver a lethal hit against diverse and difficult to-treat solid tumors.

The Weiner lab used genetic engineering combined with direct in vivo expression to create a novel dBTE which targets an important receptor on the surface of cells that initiate glioblastoma tumors. Approximately 75% of individuals with glioblastoma have a very specific receptor referred to as IL-13Ralpha2. The proof-of-concept study of IL-13Ralpha2 dBTEs on controlling glioblastoma was recently published in Molecular Therapy-Oncolytics.

“Glioblastoma is a severe disease with limited therapeutic options so the creation of novel and potentially more impactful therapeutic options for cancer patients such as the anti-glioblastoma dBTE is a major focus of Wistar’s Vaccine and Immunotherapy Center,” says David Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research.

Bispecific T cell engagers are synthetic antibodies with two chains or “arms” that can simultaneously bind an antigen expressed on a tumor and an antigen on a T cell and bring them closer together, triggering immune activation to protect the body from disease. “This redirects the activity of the T cell towards the tumor cell, attacking and killing the tumor.” explains Pratik Bhojnagarwala, graduate student in the Weiner lab and first author on the paper.

Challenges with conventional BTE treatments for cancer patients include the need for continuous IV injection over several weeks, costly treatment, and unwanted off-target issues. In this work, the team used synthetic DNA technologies to design, test and identify multiple synthetic DNA BTE forms having the most specific and potent killing activity against different glioblastoma human cancer cell lines.

It is this specific design combined with the dBTE approach that creates a kind of dBTE factory for the patient, enabling the consistent force and effectiveness of the therapy. Using this new anti-glioblastoma dBTE and direct nucleic acid encoded delivery, the researchers were able to more than double half-life of the bispecific antibodies in animal models – resulting in the clearing of tumors in vivo.

Dr. Weiner is also a leader in the development of another antibody based technology called DNA encoded monoclonal antibodies (dMAB) for treating infectious diseases including COVID-19, Zika, Ebola, and cancer. The biggest difference between dMABs and dBTEs is that dMABs encode for monoclonal antibodies that bind to a single target. DBTEs are designed to bind to two different targets at the same time and are more commonly used to engage the immune system to fight cancers. By innovating multiple types of platforms, the Weiner lab is on the forefront of translational studies harnessing basic science to fight difficult human diseases.

Bhojnagarwala plans to continue developing combination novel immunotherapies for cancer and infectious disease, specifically exploring additional designs for dBTE that can improve specificity and potency of the new approach and applying his studies towards targeting more tumor antigens for glioblastoma. He shares, “It is important for me to work in a lab where there is a high possibility that the work can rapidly be translated into clinical trials. The Weiner lab provides that platform.”

A Wistar Journey Through the Past, Present, and Future of Immunization Work

Written by The Wistar Institute on . Posted in Featured News.

Vaccines are a crucial public health tool in its’ arsenal against diseases. Resurgences of diseases long thought eradicated are popping up decades later in sewage waters here and abroad, and we’ve witnessed what the impact of war has on countries whose health systems have crumbled under the ravages of war—we are not as far removed as we’d like to be from diseases once prevented by vaccines. With more than half a century of basic research for vaccine development, The Wistar Institute plays an integral role in immunization around the globe.

Rubella, rabies, and rotavirus. Wistar scientists developed vaccines for these diseases that are used in immunization programs worldwide. The rubella vaccine by Wistar scientists effectively ended the pandemic in the United States, as declared by the CDC in 2005. Two rabies vaccinations developed from the Institute addresses the disease in both animals and humans. In 2006, Wistar and collaborators created a rotavirus vaccine which became part of the regular immunization schedule for U.S. babies and is used or approved in over 45 countries. And we’re just getting started.

“Immunization is possibly one of the most impactful medical interventions ever developed. Millions of lives are saved each year by vaccination, and we live healthier and longer lives due to vaccines.” states David Weiner, Ph.D., Executive Vice President, Director of Wistar’s Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research, in the Immunology, Microenvironment & Metastasis Program at Wistar’s Ellen and Ronald Caplan Cancer Center.

This National Immunization Awareness Month, we have shared a few snapshots of current vaccine development projects at the Institute as well as what these researchers’ hopes are for the future of immunization.

Tackling Both Infectious Disease and Cancer with Immunization

Dr. Weiner’s research takes on both infectious disease and cancer. His work encompasses developing new ways to build and deliver synthetic nucleic acid vaccines – particularly advancing a new approach that drives self-assembly of an antigen into a more potent vaccine inside a vaccinated person. This approach gives the body the genetic information to become the factory to create the vaccine. Furthermore, his lab is developing new types of cancer therapeutic vaccines with the goals of creating strong anti-cancer immunity and eradicating cancer cells.

Weiner’s collaborations with public and private institutions is centered around novel immunization technology developed from his lab called DNA-encoded monoclonal antibodies (DMAbs) against diseases such as COVID-19, Zika, and Ebola.

Regarding the future, he shares, “Together with our collaborators, we hope to move new prototype HIV vaccines into human clinical trials later this year, and continue to advance vaccines for emerging pathogens, as well as cancer immunotherapies.”

Developing DNA Vaccines

Ami Patel, Ph.D., Caspar Wistar Fellow in the Vaccine and Immunotherapy Center, focuses her scientific efforts on DNA vaccines which have potential to be more stable and economical over traditional vaccine production. “We are trying to understand how different vaccines work in the body. How do vaccines generate different types of immune responses and can we use this to understand protection against infectious diseases. We are using this information to help develop the next generation of potential vaccines.” she says.

Patel emphasizes the importance of vaccines for young children and adults by calling back to various infectious diseases like polio that are no longer very common because of immunization. “Vaccines help protect us against serious disease. Some of us remember the discomfort of chicken pox as children. There is now a vaccine.”

While she calls the COVID-19 pandemic “devastating to global health”, Patel also recognizes the pandemic’s challenges proved fertile ground for an extraordinary collaborative time for biomedical scientists. “My hope is for vaccine researchers across different disciplines to continue to work together to help us understand different infectious diseases and develop better vaccines.”

Zooming in on a Nanoscale

In collaboration with Weiner, Daniel Kulp, Ph.D., associate professor in the Vaccine and Immunotherapy Center, has embraced nanotechnology in his vaccine research. “We are developing rationally engineered nanoparticle vaccines that can elicit extremely broad coronavirus immunity providing a proof-of-concept that a pan-coronavirus vaccine is possible,” Kulp elaborates.

While the Kulp laboratory is developing several promising vaccines, he emphasizes that his goal is to assess these candidates in humans. He says, “We are working to reduce barriers for launching small experimental medicine clinical trials allowing for broader evaluation of our best vaccine concepts. Through this type of work, I have high hopes that our generation can claim credit for the eradication of SARS-CoV-2.”

Kulp expresses that “Vaccines are one of the single most effective medical technologies humans have developed saving hundreds of millions of lives. Vaccines do not work without immunizations. This message is incredibly important.”

Abs 2019-nCoV RNA virus - 3d rendered image on black background.

Collaboration Advances DNA-delivered Antibodies to Prevent COVID-19

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (July 7, 2022) — Under a Defense Advanced Research Projects Agency (DARPA) and Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) funded program, a novel COVID-19 antibody delivery approach has advanced to clinical trials. The collaborative team was led by David Weiner, Ph.D., The Wistar Institute executive vice president, director of the Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research, and included colleagues at the University of Pennsylvania, AstraZeneca, INOVIO Pharmaceuticals, and Indiana University.

This team was awarded $37.6 million to fund the rapid pre-clinical development of DNA-encoded SARs-CoV-2 monoclonal antibodies (DMAbs) to prevent COVID-19. DMAbs use a person’s own cells as a factory for making the protective antibodies, simplifying the development and the production process for biologics—which could broaden the use of such novel medicines to the global community.

The first dosing with this new investigational agent occurred in a first-in-human clinical trial being led by Pablo Tebas, M.D., professor of Infectious Diseases at the Perelman School of Medicine at the University of Pennsylvania, and his team. The clinical trial will assess the overall safety and tolerability of this novel approach to enable the body to produce multiple full-length monoclonal antibodies through advanced DNA technology in people.

“This development is the culmination of the many steps taken working together with our DARPA/JPEO leadership team and members of the consortium advancing this product at this important time. We look forward to seeing the initial outcome from this first-in-human clinical trial studying this novel concept,” Weiner shares. He elaborates on the goals of the trials, explaining “In addition to assessing safety and tolerability, we will also look for important insights into biological expression and activity in our trial subjects and if these can be shown to impact viral infection.”

“Despite all of the progress made on COVID-19 treatments and management, this disease continues to kill three times more Americans than the flu,” says Tebas. “We need better methods to prevent complications of this disease particularly in immunocompromised patients. Our study will test a new way to deliver antibodies against COVID-19 that have been proven to decrease hospitalizations and deaths from this terrible disease.”

This work is enabled through a unique public-private collaboration. The team brings together important and diverse scientific and technical strengths to create this new tool to address vulnerable patient needs. Over the past several years, Weiner and collaborators’ advances in the nucleic acid delivery space led to the developments that underpin this program. The study takes advantage of pioneering nucleic acid approaches advanced by longtime collaborator Tebas, important new tools for nucleic acid delivery developed in concert with INOVIO and is built on the collaboration with AstraZeneca to recreate protein biologics into this innovative DNA medicine approach.

Mark Esser, vice president, Early Vaccines and Immune Therapies, AstraZeneca, said, “Dosing the first patient with a COVID-19 DMAb candidate is the culmination of hard work from a collaborative public-private partnership. This trial provides an important opportunity to evaluate an innovative technology that could potentially transform how we deliver antibodies and protect against severe infections.”

The novel approach utilizes the genetic blueprints for antibodies encoded into DNA plasmids. After delivery into the arm, DMAbs instruct the body to assemble functional antibodies and secrete these into the blood as fully formed specific monoclonal antibodies against pathogens such as the SARS-CoV-2 virus. This approach bypasses the need for immunization to generate protective immunity.

Weiner says, “This project is an important example of team science and the value of working together to tackle difficult problems. The team’s mission was to advance and study a new way to deliver lifesaving therapies in a short time frame. We are hopeful that this clinical study will likely offer insight into the development of new therapeutic approaches for vulnerable patients.”

Together, the research collaboration has successfully shown evidence of SARS-CoV-2 protection in both laboratory and animal model studies with the DMAbs exhibiting the potential for both prevention and treatment of infection. In theory, this nucleic acid medicine approach has potential advantages when compared to traditional methods of monoclonal antibody treatment in aspects of cost, specificity, production, storage, and delivery, thus boosting its availability to patients more globally.

INOVIO Pharmaceuticals Chief scientific officer Laurent Humeau, Ph.D., says, “Advancing this human clinical study was made possible through the dedication of all parties involved in this consortium. We look forward to continuing to develop this promising monoclonal antibody delivery platform with our collaborators.”

This work is supported by the Office of the Assistant Secretary of Defense for Health Affairs with funding from the Defense Health Agency.

This research was developed with funding from the Defense Advanced Research Projects Agency (DARPA).

Disclaimer: The views, opinions and/or findings expressed are those of the author and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government.

Grant information: Synthetic DNA-encoded monoclonal antibodies (DMAbs) targeting COVID-19, 2020-2022, Contract #HR0011-21-9-0001.

Approved for Public Release, Distribution Unlimited

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org

Highlighting Vaccine Research at The Wistar Institute Through the Penn-CHOP-Wistar Vaccine Symposium

Written by The Wistar Institute on . Posted in Featured News.

From HIV to COVID-19, Wistar scientists are at the forefront of vaccine development. Read our recap of the recent Vaccine Symposium and the impactful research in progress at the Institute.

This past Monday, The Wistar Institute, University of Pennsylvania Perelman School of Medicine, and Children’s Hospital of Philadelphia held the Penn-CHOP-Wistar Vaccine Symposium. Hosted both in-person at the Smilow Center for Translational Research and online, the all-day event covered the history of vaccines and current vaccine research from the three sponsoring institutions.

Keynote speaker and Wistar professor emeritus Stanley Plotkin, M.D., is a prominent researcher who is known for the development of the rubella vaccine while he was a virologist at The Wistar Institute. Furthermore, his years of work helping in vaccine efforts for rabies, rotavirus, and cytomegalovirus have stimulated much innovation in the biomedical research community.
After giving a brief history of vaccines, Plotkin proclaimed “Vaccinology has taken off. … We are now in a golden age of vaccinology.”

The Symposium’s research presentations opened with Wistar’s Daniel Kulp, Ph.D., Associate Professor in the Vaccine & Immunotherapy Center, and his work on a novel COVID-19 nanoparticle vaccine. Amelia Escolano, Ph.D., Assistant Professor in the Vaccine & Immunotherapy Center, also spoke about her efforts investigating immunization strategies for HIV. Wistar’s Vaccine & Immunotherapy Center Director David B. Weiner, Ph.D., gave a summary of his research into the genetic delivery of vaccines, calling the innovation of vaccinology in Pennsylvania among these institutions “extraordinary”.

The current global pandemic has reinforced the need for scientific solutions and a deeper understanding of human diseases. It is the studies and ideas from research centers like The Wistar Institute and its colleagues that propel forward biomedicine. As keynote speaker Plotkin stated, “Pandemics have occurred throughout the history of humankind and will continue to do so in the future. Infectious diseases of humans will continue to happen. Therefore, we must act against them.”

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

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

Written by The Wistar Institute on . Posted in Featured News.

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

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

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

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

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

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

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

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

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