Tag: immunology

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An Improved Delivery System for mRNA Vaccines Provides More Powerful Protection

by Devorah Fischler

(From left to right) Xuexiang Han, Michael Mitchell and Mohamad-Gabriel Alameh

The COVID-19 vaccine swiftly undercut the worst of the pandemic for hundreds of millions around the world. Available sooner than almost anyone expected, these vaccines were a triumph of resourcefulness and skill.

Messenger RNA vaccines, like the ones manufactured by Moderna or Pfizer/BioNTech, owed their speed and success to decades of research reinforcing the safety and effectiveness of their unique immune-instructive technology.

Now, researchers from the University of Pennsylvania School of Engineering and Applied Science and the Perelman School of Medicine are refining the COVID-19 vaccine, creating an innovative delivery system for even more robust protection against the virus.

In addition to outlining a more flexible and effective COVID-19 vaccine, this work has potential to increase the scope of mRNA vaccines writ large, contributing to prevention and treatment for a range of different illnesses.

Michael Mitchell, associate professor in Penn Engineering’s Department of Bioengineering, Xuexiang Han, postdoctoral fellow in Mitchell’s lab, and Mohamad-Gabriel Alameh, postdoctoral fellow in Drew Weissman’s lab at Penn Medicine and incoming assistant professor in the Department of Pathology and Laboratory Medicine at the Perelman School of Medicine, recently published their findings in Nature Nanotechnology.

mRNA, or messenger ribonucleic acid, is the body’s natural go-between. mRNA contains the instructions our cells need to produce proteins that play important roles in our bodies’ health, including mounting immune responses.

The COVID-19 vaccines follow suit, sending a single strand of RNA to teach our cells how to recognize and fight the virus.

Read the full story in Penn Engineering Today.

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For a New Generation of Antibiotics, Scientists are Bringing Extinct Molecules Back to Life – and Discovering the Hidden Genetics of Immunity Along the Way

by Devorah Fischler

Marrying artificial intelligence with advanced experimental methods, the Machine Biology Group has mined the ancient past for future medical breakthroughs, bringing extinct molecules back to life. (Image credit: Ella Marushchenko)

“We need to think big in antibiotics research,” says Cesar de la Fuente. “Over one million people die every year from drug-resistant infections, and this is predicted to reach 10 million by 2050. There hasn’t been a truly new class of antibiotics in decades, and there are so few of us tackling this issue that we need to be thinking about more than just new drugs. We need new frameworks.”

De la Fuente is Presidential Assistant Professor in the Department of Bioengineering and the Department of Chemical and Biomolecular Engineering at the University of Pennsylvania School of Engineering and Applied Science. He holds additional primary appointments in Psychiatry and Microbiology in the Perelman School of Medicine.

De la Fuente’s lab, the Machine Biology Group, creates these new frameworks using potent partnerships in engineering and the health sciences, drawing on the “power of machines to accelerate discoveries in biology and medicine.”

Marrying artificial intelligence with advanced experimental methods, the group has mined the ancient past for future medical breakthroughs. In a recent study published in Cell Host and Microbe, the team has launched the field of “molecular de-extinction.”

Our genomes – our genetic material – and the genomes of our ancient ancestors, express proteins with natural antimicrobial properties. “Molecular de-extinction” hypothesizes that these molecules could be prime candidates for safe new drugs. Naturally produced and selected through evolution, these molecules offer promising advantages over molecular discovery using AI alone.

In this paper, the team explored the proteomic expressions of two extinct organisms –Neanderthals and Denisovans, archaic precursors to the human species – and found dozens of small protein sequences with antibiotic qualities. Their lab then worked to synthesize these molecules, bringing these long-since-vanished chemistries back to life.

“The computer gives us a sequence of amino acids,” says de la Fuente. “These are the building blocks of a peptide, a small protein. Then we can make these molecules using a method called ‘solid-phase chemical synthesis.’ We translate the recipe of amino acids into an actual molecule and then build it.”

The team next applied these molecules to pathogens in a dish and in mice to test the veracity and efficacy of their computational predictions.

“The ones that worked, worked quite well,” continues de la Fuente. “In two cases, the peptides were comparable – if not better – than the standard of care. The ones that didn’t work helped us learn what needed to be improved in our AI tools. We think this research opens the door to new ways of thinking about antibiotics and drug discovery, and this first step will allow scientists to explore it with increasing creativity and precision.”

Read the full story in Penn Engineering Today.

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Why New Cancer Treatments are Proliferating

by Karen L. Brooks

Doctors performing surgery.
Image: Penn Medicine News

In the five years since the FDA’s initial approval of chimeric antigen receptor (CAR) T cell therapy, Penn Medicine has gleaned 20 additional approvals related to drugs and techniques to treat or detect cancer.

Rather than being the single disease class many people refer to, “cancer” is a blanket term that covers more than 100 distinct diseases, many of which have little in common aside from originating with rapidly dividing cells. Since different cancers demand different treatments, it follows that any given new therapy emerging from any institution would be likely to be a new cancer treatment.

But why so many in just this five-year period?

The volume of new cancer treatments makes sense, says Abramson Cancer Center (ACC) director Robert Vonderheide, attributing the flurry of new cancer drug approvals to a recent “explosion” in knowledge about cancer biology.

“Much of that knowledge is about the immune system’s ability to attack cancer, which people seriously doubted until about 20 years ago. As soon as we had a clinical validation for this Achilles heel in cancer, the dam burst for ideas about other ways to exploit that vulnerability to come forward,” he says. “The first drug that came out to activate the immune system inspired the rest of the field to find the next drug, and the one after that. We as a field have moved from serendipity and empiricism to science-driven drug design.”

The first CAR T cell therapy approval invigorated Penn faculty interested in finding new ways to harness the immune system to fight cancer.

“An approval like that makes what you’re working on more of a reality,” says Avery Posey, an assistant professor of systems pharmacology and translational therapeutics in the Perelman School of Medicine, whose lab team spends much of its time trying to identify more specific antigens for solid tumors and also studies ways to optimize engineered donor T cells. “It brings a new perspective, showing that your work is more than basic research and can actually become drugs that impact patients’ lives. That’s a real motivator to keep pushing forward.”

Honing new immunotherapies is a priority among Penn researchers, but not every recently approved new cancer treatment or detection tool developed at the institution engages the immune system. Faculty have explored and introduced widely varying approaches to improving the standard of care for cancer patients.

Read the full story in Penn Medicine Magazine.

Avery Posey is a member of the Penn Bioengineering Graduate Group. Read more stories featuring Posey here.

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Penn Bioengineering Graduate Student on T Cell Therapy Improvements

Image: Courtesy of Penn Medicine News

 Neil Sheppard,  Adjunct Associate Professor of Pathology and Laboratory Medicine in the Perelman School of Medicine, and David Mai, a Bioengineering graduate student in the School of Engineering and Applied Science, explained the findings of their recent study, which offered a potential strategy to improve T cell therapy in solid tumors, to the European biotech news website Labiotech.

Mai is a graduate student in the lab of Carl H. June, the Richard W. Vague Professor in Immunotherapy in Penn Medicine, Director of the Center for Cellular Immunotherapies (CCI) at the Abramson Cancer Center, and member of the Penn Bioengineering Graduate Group.

Read “Immunotherapy in the fight against solid tumors” in Labiotech.

Read more about this collaborative study here.

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Carl H. June, MD, FAACR, Honored with 2023 AACR Award for Lifetime Achievement in Cancer Research

Carl June, MD

 The American Association for Cancer Research (AACR), the largest cancer research organization in the country and based in Philadelphia, will bestow its 2023 Award for Lifetime Achievement in Cancer Research to Carl June, Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine at Penn Medicine. June is also Director of the Center for Cellular Immunotherapies, Director of the Parker Institute for Cancer Immunotherapy, and member of the Penn Bioengineering Graduate Group. He is recognized for his groundbreaking work in developing the first gene-editing cell therapy for cancer and for his pioneering work with CAR T cell therapy.

Read the press release on the AACR website.

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A Potential Strategy to Improve T Cell Therapy in Solid Tumors

A new Penn Medicine preclinical study demonstrates a simultaneous ‘knockout’ of two inflammatory regulators boosts T cell expansion to attack solid tumors.

by Meagan Raeke

Image: Courtesy of Penn Medicine News

A new approach that delivers a “one-two punch” to help T cells attack solid tumors is the focus of a preclinical study by researchers from the Perelman School of Medicine. The findings, published in the Proceedings of the National Academy of Sciences, show that targeting two regulators that control gene functions related to inflammation led to at least 10 times greater T cell expansion in models, resulting in increased anti-tumor immune activity and durability.

CAR T cell therapy was pioneered at Penn Medicine by Carl H. June, the Richard W. Vague Professor in Immunotherapy at Penn and director of the Center for Cellular Immunotherapies (CCI) at Abramson Cancer Center, whose work led to the first approved CAR T cell therapy for B-cell acute lymphoblastic leukemia in 2017. Since then, personalized cellular therapies have revolutionized blood cancer treatment, but remained stubbornly ineffective against solid tumors, such as lung cancer and breast cancer.

“We want to unlock CAR T cell therapy for patients with solid tumors, which include the most commonly diagnosed cancer types,” says June, the new study’s senior author. “Our study shows that immune inflammatory regulator targeting is worth additional investigation to enhance T cell potency.”

One of the challenges for CAR T cell therapy in solid tumors is a phenomenon known as T cell exhaustion, where the persistent antigen exposure from the solid mass of tumor cells wears out the T cells to the point that they aren’t able to mount an anti-tumor response. Engineering already exhausted T cells from patients for CAR T cell therapy results in a less effective product because the T cells don’t multiply enough or remember their task as well.

Previous observational studies hinted at the inflammatory regulator Regnase-1 as a potential target to indirectly overcome the effects of T cell exhaustion because it can cause hyperinflammation when disrupted in T cells—reviving them to produce an anti-tumor response. The research team, including lead author David Mai, a bioengineering graduate student in the School of Engineering and Applied Science, and co-corresponding author Neil Sheppard, head of the CCI T Cell Engineering Lab, hypothesized that targeting the related, but independent Roquin-1 regulator at the same time could boost responses further.

“Each of these two regulatory genes has been implicated in restricting T cell inflammatory responses, but we found that disrupting them together produced much greater anti-cancer effects than disrupting them individually,” Mai says. “By building on previous research, we are starting to get closer to strategies that seem to be promising in the solid tumor context.”

Read the full story in Penn Medicine News.

June is a member of the Penn Bioengineering Graduate Group. Read more stories featuring June’s research here.

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Inside the Jiang Lab: An Inventory of Immunity

by Olivia J. McMahon

Black and white photo of Jenny Jiang working in her lab on a laptop.
Jenny Jiang, Ph.D.

Engineers in the Center for Precision Engineering for Health (CPE4H) are focusing on innovations in diagnostics and delivery, cellular and tissue engineering, and the development of new devices that integrate novel materials with human tissues. Below is an excerpt from “Going Small to Win Big: Engineering Personalized Medicine,” featuring the research from the laboratory of Jenny Jiang, J. Peter and Geri Skirkanich Associate Professor of Innovation in Bioengineering.

The Challenge

In order to create personalized immune therapies, researchers need to untangle what is happening between an individual patient’s immune cells and the antigens that they interact with on a molecular level. Immune cell-antigen interactions need to be understood in four different areas in order to create a full picture: the unique genetic sequence of the T cell’s antigen receptors, the antigen specificity of that cell, and both the gene and protein expression of the same cell.

The Status Quo

Prior methods of understanding interactions between T cells and antigens could only get a picture of one or two of these four elements because of technology constraints. Other roadblocks included that cells cultured or engineered in a laboratory setting are not in a natural environment so they won’t express genes or proteins in the way T cells would in the body, and technologies that assess the antigen specificity of T cells were not cost-effective for looking at large numbers of antigens.

The Jiang Lab’s Fix

The lab of Jenny Jiang, J. Peter and Geri Skirkanich Associate Professor of Innovation in Bioengineering, developed a technology called TetTCR-SeqHD, which solves these problems. Using this technology, scientists can now simultaneously profile samples of large numbers of single T cells in the four dimensions using high- throughput screening.

The Jiang Lab’s technology is essentially a method for getting a “full-body scan” of an individual’s T cells and creates a catalog of the different types of T cells and the antigens they respond (or don’t respond) to, paving the way for the ability to better target immune therapies to an individual patient.

“Individual T cells are unique, and that’s the challenge of using one treatment to fit all,” says Jiang. “Identifying antigen specificity and creating therapies that target that specificity in an individual’s T cells will be key to truly personalizing immune therapies in the future.”

Read the full story in Penn Engineering magazine.

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CAR T Cell Therapy Reaches Beyond Cancer

Penn Medicine researchers laud the early results for CAR T therapy in lupus patients, which point to broader horizons for the use of personalized cellular therapies.

Penn Medicine’s Carl June and Daniel Baker.

Engineered immune cells, known as CAR T cells, have shown the world what personalized immunotherapies can do to fight blood cancers. Now, investigators have reported highly promising early results for CAR T therapy in a small set of patients with the autoimmune disease lupus. Penn Medicine CAR T pioneer Carl June and Daniel Baker, a doctoral student in cell and molecular biology in the Perelman School of Medicine, discuss this development in a commentary published in Cell.

“We’ve always known that in principle, CAR T therapies could have broad applications, and it’s very encouraging to see early evidence that this promise is now being realized,” says June, who is the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine at Penn Medicine and director of the Center for Cellular Immunotherapies at the Abramson Cancer Center.

T cells are among the immune system’s most powerful weapons. They can bind to, and kill, other cells they recognize as valid targets, including virus-infected cells. CAR T cells are T cells that have been redirected, through genetic engineering, to efficiently kill specifically defined cell types.

CAR T therapies are created out of each patient’s own cells—collected from the patient’s blood, and then engineered and multiplied in the lab before being reinfused into the patient as a “living drug.” The first CAR T therapy, Kymriah, was developed by June and his team at Penn Medicine, and received Food & Drug Administration approval in 2017. There are now six FDA-approved CAR T cell therapies in the United States, for six different cancers.

From the start of CAR T research, experts believed that T cells could be engineered to fight many conditions other than B cell cancers. Dozens of research teams around the world, including teams at Penn Medicine and biotech spinoffs who are working to develop effective treatments from Penn-developed personalized cellular therapy constructs, are examining these potential new applications. Researchers say lupus is an obvious choice for CAR T therapy because it too is driven by B cells, and thus experimental CAR T therapies against it can employ existing anti-B-cell designs. B cells are the immune system’s antibody-producing cells, and, in lupus, B cells arise that attack the patient’s own organs and tissues.

This story is by Meagan Raeke. Read more at Penn Medicine News.

Carl June is a member of the Penn Bioengineering Graduate Group. Read more stories featuring June’s research here.

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2022 Career Award Recipient: Michael Mitchell

by Melissa Pappas

Michael Mitchell (Illustration by Melissa Pappas)

Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, is one of this year’s recipients of the National Science Foundation’s CAREER Award. The award is given to early-career faculty researchers who demonstrate the potential to be role models in their field and invest in the outreach and education of their work.

Mitchell’s award will fund research on techniques for “immunoengineering” macrophages. By providing new instructions to these cells via nanoparticles laden with mRNA and DNA sequences, the immune system could be trained to target and eliminate solid tumors. The award will also support graduate students and postdoctoral fellows in his lab over the next five years.

The project aligns with Mitchell’s larger research goals and the current explosion of interest in therapies that use mRNA, thanks to the technological breakthroughs that enabled the development of COVID-19 vaccines.

“The development of the COVID vaccine using mRNA has opened doors for other cell therapies,” says Mitchell. “The high-priority area of research that we are focusing on is oncological therapies, and there are multiple applications for mRNA engineering in the fight against cancer.”

A new wave of remarkably effective cancer treatments incorporates chimeric antigen receptor T-cell (CAR-T) therapy. There, a patient’s T-cells, a type of white blood cell that fights infections, are genetically engineered to identify, target and kill individual cancer cells that accumulate in the circulatory system.

However, despite CART-T therapy’s success in treating certain blood cancers, the approach is not effective against cancers that form solid tumors. Because T-cells are not able to penetrate tumors’ fibrous barriers, Mitchell and his colleagues have turned to another part of the immune system for help.

Read the full story in Penn Engineering Today.

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Penn Medicine CAR T Therapy Expert Carl June Receives 2022 Keio Medical Science Prize

by Brandon Lausch

The award from Japan’s oldest private university honors outstanding contributions to medicine and life sciences.

Richard W. Vague Professor in Immunotherapy Carl June.

Carl June, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine in the Perelman School of Medicine and director of the Center for Cellular Immunotherapies at Penn’s Abramson Cancer Center, has been named a 2022 Keio Medical Science Prize Laureate. He is recognized for his pioneering role in the development of CAR T cell therapy for cancer, which uses modified versions of patients’ own immune cells to attack their cancer.

The Keio Medical Science Prize is an annual award endowed by Keio University, Japan’s oldest private university, which recognizes researchers who have made an outstanding contribution to the fields of medicine or the life sciences. It is the only prize of its kind awarded by a Japanese university, and eight laureates of this prize have later won the Nobel Prize. Now in its 27th year, the prize encourages the expansion of researcher networks throughout the world and contributes to the well-being of humankind.

“Dr. June exemplifies the spirit of curiosity and fortitude that make Penn home to so many ‘firsts’ in science and medicine,” said Penn President Liz Magill. “His work provides hope to cancer patients and their families across the world, and inspiration to our global community of physicians and scientists who are working to develop the next generation of treatments and cures for diseases of all kinds.”

Read the full story in Penn Today.

June is a member of the Penn Bioengineering Graduate Group. Read more stories featuring June’s research here.