Tag: cancer

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Secondary Cancers Following CAR T Cell Therapy Are Rare, Penn Medicine Analysis Shows

by Meagan Raeke

3d illustration of a damaged and disintegrating cancer cell. (Image: iStock/vitanovski)

The development of any type of second cancer following CAR T cell therapy is a rare occurrence, as found in an analysis of more than 400 patients treated at Penn Medicine, researchers from the Perelman School of Medicine at the University of Pennsylvania reported today in Nature Medicine. The team also described a single case of an incidental T cell lymphoma that did not express the CAR gene and was found in the lymph node of a patient who developed a secondary lung tumor following CAR T cell therapy.

CAR T cell therapy, a personalized form of immunotherapy in which each patient’s T cells are modified to target and kill their cancer cells, was pioneered at Penn. More than 30,000 patients with blood cancers in the United States—many of whom had few, if any, remaining treatment options available—have been treated with CAR T cell therapy since the first such therapy was approved in 2017. Some of the earliest patients treated in clinical trials have gone on to experience long-lasting remissions of a decade or more.

Secondary cancers, including T cell lymphomas, are a known, rare risk of several types of cancer treatment, including chemotherapy, radiation, and stem cell transplant. CAR T cell therapy is currently only approved to treat blood cancers that have relapsed or stopped responding to treatment, so patients who receive CAR T cell therapies have already received multiple other types of treatment and are facing dire prognoses.

In November 2023, the FDA announced an investigation into several reported cases of secondary T cell malignancies, including CAR-positive lymphoma, in patients who previously received CAR T cell therapy products. In January 2024, the FDA began requiring drugmakers to add a safety label warning to CAR T cell products. While the FDA review is still ongoing, it remains unclear whether the secondary T cell malignancies were caused by CAR T cell therapy.

As a leader in CAR T cell therapy, Penn has longstanding, clearly established protocols to monitor each patient both during and after treatment – including follow-up for 15 years after infusion – and participates in national reporting requirements and databases that track outcomes data from all cell therapy and bone marrow transplants.

Marco Ruella, M.D.

“When this case was identified, we did a detailed analysis and concluded the T cell lymphoma was not related to the CAR T cell therapy. As the news of other cases came to light, we knew we should go deeper, to comb through our own data to better understand and help define the risk of any type of secondary cancer in patients who have received CAR T cell products,” said senior author Marco Ruella, MD, an assistant professor of Hematology-Oncology and Scientific Director of the Lymphoma Program. “What we found was very encouraging and reinforces the overall safety profile for this type of personalized cell therapy.”

Read the full story in Penn Medicine News.

Marco Ruella is Assistant Professor of Medicine in the Perelman School of Medicine. He is a member of the Penn Bioengineering Graduate Group.

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Sydney Shaffer Wins Christopher J. Marshall Award for Melanoma Research

Sydney Shaffer, M.D., Ph.D.

Sydney Shaffer, Assistant Professor in Bioengineering in the School of Engineering and Applied Science and in Pathology and Laboratory Medicine in the Perelman School of Medicine, was named the 2023 Christopher J. Marshall Award winner by the Society for Melanoma Research (SMR). The award recognizes Shaffer’s contributions to melanoma research on oncogenic signalling and molecular pathogenesis of this disease, as well as her rapid development as a rising star and leader in the field, which have helped to further the SMR’s goal to eradicate melanoma. The award was presented at the SMR annual meeting in Philadelphia in November 2023. 

The Christopher J. Marshall Award was established in 2015 by the SMR in partnership with Melanoma Research Foundation Congress to recognize a student, postdoctoral fellow, or new independent PI who has published a substantial and original contribution to studies of signal transduction and melanoma.

Shaffer joined Penn as an Assistant Professor in 2019. She holds a M.D.-Ph.D. in Medicine and Bioengineering from the University of Pennsylvania and conducted postdoctoral research in cancer biology in the lab of Junwei Shi, Associate Professor in Penn Medicine. The Syd Shaffer Lab is an interdisciplinary team which focuses on “understanding how differences between single-cells generate phenotypes such as drug resistance, oncogenesis, differentiation, and invasion [using] a combination of imaging and sequencing technologies to investigate rare single-cell phenomena.” A recent paper in Nature Communications details the team’s method to quantify long-lived fluctuations in gene expression that are predictive of later resistance to targeted therapy for melanoma.

Read the award announcement and the full list of prior winners at the SMR website.

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Arjun Raj Receives 2023-24 Heilmeier Award

by Olivia J. McMahon

Arjun Raj, Ph.D.

Arjun Raj, Professor in Bioengineering in Penn Engineering, has been named the recipient of the 2023-24 George H. Heilmeier Faculty Award for Excellence in Research for “pioneering the development and application of single-cell, cancer-fighting technologies.”

The Heilmeier Award honors a Penn Engineering faculty member whose work is scientifically meritorious and has high technological impact and visibility. It is named for the late George H. Heilmeier, a Penn Engineering alumnus and member of the School’s Board of Advisors, whose technological contributions include the development of liquid crystal displays and whose honors include the National Medal of Science and Kyoto Prize.

Raj, who also holds an appointment in Genetics in the Perelman School of Medicine, is a pioneer in the burgeoning field of single-cell engineering and biology. Powered by innovative techniques he has developed for molecular profiling of single cells, his scientific discoveries range from the molecular underpinnings of cellular variability to the behavior of single cells across biology, including in diseases such as cancer.

Raj will deliver the 2023-24 Heilmeier Lecture at Penn Engineering during the spring 2024 semester.

This story originally appeared in Penn Engineering Today.

Read more stories featuring Dr. Raj here.

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Leveraging the Body’s Postal System to Understand and Treat Disease

by Nathi Magubane

Microwell device with a solution in the reservoir (Image: Courtesy of David E. Reynolds)

Akin to the packages sent from one person to another via an elaborate postal system, cells send tiny parcels that bear contents and packaging material that serve key purposes: To protect the contents from the outside world and to make sure it gets to the right place via a label with an address. 

These packages are known as extracellular vesicles (EVs)—lipid-bound molecules that serve a variety of regulatory and maintenance functions throughout the body. They assist in the removal of unwanted materials within the cell, and they transport proteins, aid in DNA and RNA transfer, and promote tumorigeneses in cancerous cells. 

Given their myriad roles, EVs have taken center stage for many researchers in the biomedical space as they have the potential to improve current methods of disease detection and treatment. The main challenge, however, is accurately identifying the molecular contents of EVs while also characterizing the EVs, which, unlike other cellular components that are more homogenous, have more heterogeneity.

Now, a team of researchers at the University of Pennsylvania has developed a novel platform, droplet-free double digital assay, for not only profiling individual EVs but also accurately discerning their molecular contents. The researchers took the digital assay, which quantifies the contents of a molecule via binary metric—a 1 corresponds to the presence of a molecule and a zero to the lack thereof—and applies it to the EV. The work is published in Advanced Science.

The team was led by Jina Ko, an assistant professor with appointments in the School of Engineering and Applied Science and Perelman School of Medicine. “Our method allows for highly accurate quantification of the individual molecules inside an EV,” Ko says . “This opens up many doors in the realm of early disease detection and treatment.”

The researchers first compartmentalized individual EVs utilizing a microwell approach to isolate the EVs. Next, they captured individual molecules within the EVs and amplified the signal for clarity. The team then was able to determine the expression levels of pivotal EV biomarkers with remarkable precision via fluorescence.

Read the full story in Penn Today.

Jina Ko is an assistant professor in the Department of Pathology and Laboratory Medicine in the Perelman School of Medicine and an assistant professor in the Department of Bioengineering in the School of Engineering and Applied Science at the University of Pennsylvania.

David Reynolds is a Ph.D. candidate in the Department of Bioengineering in Penn Engineering.

Other authors include, Menghan Pan, George Galanis, Yoon Ho Roh, Renee-Tyler T. Morales, Shailesh Senthil Kumar, and Su-Jin Heo of the Department of Bioengineering at Penn Engineering; Jingbo Yang and Xiaowei Xu of the Department of Pathology and Laboratory Medicine at Penn Medicine; and Wei Guo of the Department of Biology in the School of Arts & Sciences at Penn.

The research was supported by the National Institutes of Health: grants R00CA256353, R35 GM141832, and CA174523 (SPORE).

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The Immune Health Future, Today

by Christina Hernandez Sherwood

Breaking the code of the immune system could provide a new fundamental way of understanding, treating, and preventing every type of disease. Penn Medicine is investing in key discoveries about immunity and immune system function, and building infrastructure, to make that bold idea a reality.

Several members of the Penn Bioengineering Graduate Group feature in this story which originally featured in the Penn Medicine Magazine.

Image: Courtesy of Penn Medicine Magazine

This grandfather lives with primary progressive multiple sclerosis (MS), an autoimmune disorder that he controls with a medicine that depletes his body of the type of immune cells that make antibodies. So while he has completed his COVID-19 vaccine course, his immune system function isn’t very strong—and the invitation has arrived at a time when COVID-19 is still spreading rapidly. 

You can imagine the scene as an older gentleman lifts a thick, creamy envelope from his mailbox, seeing his own name written in richly scripted lettering. He beams with pride and gratitude at the sight of his granddaughter’s wedding invitation. Yet his next thought is a sober and serious one. Would he be taking his life in his hands by attending the ceremony?

“In the past, all we could do was [measure] the antibody response,” says Amit Bar-Or, the Melissa and Paul Anderson President’s Distinguished Professor in Neurology at the Perelman School of Medicine, and chief of the Multiple Sclerosis division. “If that person didn’t have a good antibody response, which is likely because of the treatment they’re on, we’d shrug our shoulders and say, ‘Maybe you shouldn’t go because we don’t know if you’re protected.’” 

Today, though, Bar-Or can take a deeper dive into his patients’ individual immune systems to give them far more nuanced recommendations. A clinical test for immune cells produced in response to the COVID-19 vaccine or to the SARS-CoV-2 virus itself—not just antibodies—was one of the first applied clinical initiatives of a major new Immune Health® project at Penn Medicine. Doctors were able to order this test and receive actionable answers through the Penn Medicine electronic health record for patients like the grandfather with MS. 

“With a simple test and an algorithm we can have a very different discussion,” Bar-Or says. A test result showing low T cells, for instance, would tell Bar-Or his patient may get a meaningful jolt in immunity from a vaccine booster, while low antibody levels would suggest passive antibody therapy is more helpful. Or, the test might show his body is already well primed to protect him, making it reasonably safe to attend the wedding.

This COVID-19 immunity test is only the beginning. 

Physicians and scientists at Penn Medicine are imagining a future where patients can get a precise picture of their immune systems’ activity to guide treatment decisions. They are working to bring the idea of Immune Health to life as a new area of medicine. In labs, in complex data models, and in the clinic, they are beginning to make sense out of the depth and breadth of the immune system’s millions of as-yet-undeciphered signals to improve health and treat illnesses of all types. 

Penn Medicine registered the trademark for the term “Immune Health” in recognition of the potential impact of this research area and its likelihood to draw non-academic partners as collaborators in its growth. Today, at the south end of Penn’s medical campus, seven stories of research space are being added atop an office building at 3600 Civic Center Blvd., including three floors dedicated to Immune Health, autoimmunity, and immunology research.

The concept behind the whole project, says E. John Wherry, director of Penn Medicine’s Institute for Immunology and Immune Health (I3H), “is to listen to the immune system, to profile the immune system, and use those individual patient immune fingerprints to diagnose and treat diseases as diverse as immune-related diseases, cancer, cardiovascular disease, Alzheimer’s, and many others.”

The challenge is vast. Each person’s immune system is far more complex than antibodies and T cells alone. The immune system is made of multiple interwoven layers of complex defenders—from our skin and mucous membranes to microscopic memory B cells that never forget a childhood infection—meant to fortify our bodies from germs and disease. It is a sophisticated system that learns and adapts over our lifetimes in numerous ways, and it also falters and fails in some ways we understand and others that remain mysterious. And each person’s intricate internal battlefield is in some way unique.

The immune system is not just a set of defensive barricades, either. It’s also a potential source of deep insight about a person’s physiological functioning and responses to medical treatments.

“The immune system is sensing and keeping track of basically all tissues and all cells in our body all the time,” Wherry says. “It is surveying the body trying to clean up any invaders and restore homeostasis by maintaining good health.”

“Our goal is to essentially break the code of the immune system,” says Jonathan Epstein, executive vice dean of the Perelman School of Medicine and chief scientific officer at Penn Medicine. “By doing so, we believe we will be able to determine your state of health and your response to therapies in essentially every human disease.”

Read the full story in Penn Today.

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Innovation and Impact: “RNA: Past, Present and Future”

by Melissa Pappas

(Left to right): Mike Mitchell, Noor Momin, and David Meaney recording the Innovation & Impact podcast.

In the most recent episode of the Penn Engineering podcast Innovation & Impact, titled “RNA: Past, Present and Future,” David F. Meaney, Senior Associate Dean of Penn Engineering and Solomon R. Pollack Professor in Bioengineering, is joined by Mike Mitchell, Associate Professor in Bioengineering, and Noor Momin, who will be joining Penn Engineering as an Assistant Professor in Bioengineering early next year, to discuss the impact that RNA has had on health care and biomedical engineering technologies.

Mitchell outlines his lab’s research that spans drug delivery, new technology in protecting RNA and its applications in treating cancer. Momin details her research, which is focused on optimizing the immune system to protect against illnesses such as cardiovascular diseases and cancer. With Meaney driving the discussion around larger questions, including the possibility of a cancer vaccine, the three discuss what they are excited about now and where the field is going in the future with these emerging, targeted treatments.

Read the full story in Penn Engineering Today.

Subscribe to the Innovation & Impact podcast on Apple Music, Spotify or your favorite listening platforms or find all the episodes on the Penn Engineering YouTube channel.

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Bioengineering Faculty Member Named ‘Young Innovator’ for Creation of Multiple Myeloma Therapy

by Abbey Porter

Michael Mitchell

Michael J. Mitchell, Associate Professor in Bioengineering at the University of Pennsylvania School of Engineering and Applied Science, has been named a “Young Innovator of Cellular and Molecular Bioengineering” by Cellular and Molecular Bioengineering, the journal of the Biomedical Engineering Society (BMES).

The award recognizes faculty who are conducting some of the most innovative and impactful studies in the field of biomedical engineering. Recipients will present their research and be officially recognized at the BMES Annual Meeting in October.

Mitchell is being honored for creating an RNA nanoparticle therapy that stops the spread of the deadly bone marrow cancer multiple myeloma and helps to eliminate it altogether. Known for being difficult to treat, the disease kills over 100,000 people every year.

“We urgently need innovative, effective therapies against this cancer,” Mitchell says. “The nanotechnology we developed can potentially serve as a platform to treat multiple myeloma and other bone marrow-based malignancies.”

Mitchell, along with Christian Figuerora-Espada, a doctoral student in Bioengineering, previously published a study in PNAS describing how their RNA nanoparticle therapy stops multiple myeloma from moving through the blood vessels and mutating. In their current paper in Cellular and Molecular Bioengineering, which expands upon this RNA nanoparticle platform, they show that inhibition of both multiple myeloma migration and adhesion to bone marrow blood vessels, combined with an FDA-approved multiple myeloma therapeutic, extends survival in a mouse model of multiple myeloma.

Read more in Penn Engineering Today.

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Carl June to Receive 2024 Breakthrough Prize in Life Sciences

by Meagan Raeke

Image: Courtesy of Penn Medicine

CAR T cell therapy pioneer Carl June, the Richard W. Vague Professor in Immunotherapy in the Perelman School of Medicine and director of the Center for Cellular Immunotherapies (CCI) at Penn Medicine’s Abramson Cancer Center, has been named a winner of the 2024 Breakthrough Prize in Life Sciences for the development of chimeric antigen receptor (CAR) T cell immunotherapy, a revolutionary cancer treatment approach in which each patient’s T cells are modified to target and kill their cancer cells. The invention sparked a new path in cancer care, harnessing the power of patients’ own immune systems, a once-elusive goal that brought fresh options for those who could not be successfully treated with conventional approaches.

Founded in 2012, the Breakthrough Prizes are the world’s largest science awards, with $3 million awarded for each of the five main prize categories. June is the sixth Breakthrough Prize laureate from Penn, which joins Harvard and MIT among the institutions whose researchers have been honored with the most Breakthrough Prizes.

“This award is not only a testament to Dr. June’s outstanding contributions to science, but also a shining example of the caliber of discoveries and research which Penn faculty set their sights upon,” said Penn President Liz Magill. “We are immensely proud to have Dr. June as a member of the Penn academic community, and we know that CAR T cell therapy is just the first chapter in an inspiring and lifesaving new era of medicine.”

June is internationally recognized for his role in pioneering the CAR T cell therapy, which led to the first FDA-approved personalized cellular therapy, for children and young adults with the blood cancer known as acute lymphoblastic leukemia, in August of 2017—a step which has spurred five additional approvals of the technique in other blood cancers. June joined Penn in 1999, building momentum for Penn to become a global hub for cell and gene therapy. Gene-modified T cells engineered in June’s lab to retrain a patient’s own immune cells to attack cancer were used in the first clinical trial of CAR T cell therapy in 2010. Some of the earliest children and adults treated have experienced long-lasting remissions of 10 years or more. In addition to the FDA approvals that have made the therapy commercially available to patients across the world, thousands more have benefited from clinical trials testing these transformative treatments, including for the treatment of solid tumors and even autoimmune diseases like lupus.

“Dr. June’s tireless commitment to advancing T cell immunotherapy research has been life-changing for many patients affected by cancer, who have lived longer, fuller lives, thanks to the discoveries made in his lab,” said J. Larry Jameson,executive vice president of the University of Pennsylvania for the Health System and dean of the Perelman School of Medicine. “We are proud to see one of Penn’s most esteemed scientists recognized for the impact of his foundational work to develop a new class of cancer immunotherapy treatment.”

Read the full story in Penn Today.

June is a member of the Penn Bioengineering Graduate Group. Read more stories featuring June on the BE Blog here.

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A Suit of Armor for Cancer-fighting Cells

by Nathi Magubane

Chimeric antigen receptor T cell (CAR T) therapy has delivered promising results, transforming the fight against various forms of cancer, but for many, the therapy comes with severe and potentially lethal side effects. Now, a research team led by Michael Mitchell of the School of Engineering and Applied Science has found a solution that could help CAR T therapies reach their full potential while minimizing severe side effects. (Image: iStock / Meletios Verras)

In recent years, cancer researchers have hailed the arrival of chimeric antigen receptor T cell (CAR T) therapy, which has delivered promising results, transforming the fight against various forms of cancer. The process involves modifying patients’ T-cells to target cancer cells, resulting in remarkable success rates for previously intractable forms of cancer.

Six CAR T cell therapies have secured FDA approval, and several more are in the pipeline. However, these therapies come with severe and potentially lethal side effects, namely cytokine release syndrome (CRS) and neurotoxicity. These drawbacks manifest as a range of symptoms—from high fever and vomiting to multiple organ failure and patient death—posing significant challenges to broader clinical application.

Now, a research team led by Michael Mitchell, associate professor in the School of Engineering and Applied Science at the University of Pennsylvania, has found a solution that could help CAR T therapies reach their full potential while minimizing severe side effects. Their findings are published in the journal Nature Materials.

“Addressing CRS and neurotoxicity without compromising the therapeutic effectiveness of CAR T cells has been a complex challenge,” says Mitchell.

He says that unwanted interactions between CAR T and immune cells called macrophages drive the overactivation of macrophages, which in turn result in the release of toxic cytokines that lead to CRS and neurotoxicity.

“Controlling CAR T-macrophage interactions in vivo is difficult,” Mitchell says. “So, our study introduces a materials engineering-based strategy that involves incorporating a sugar molecule onto the surface of CAR T cells. These sugars are then used as a reactive handle to create a biomaterial coating around these cells directly in the body, which acts as a ‘suit of armor,’ preventing dangerous interactions with macrophages.”

First author Ningqiang Gong, a postdoctoral researcher in the Mitchell Lab, elaborates on the technique, “We attached this sugar molecule to the CAR T cells using metabolic labeling. This modification enables the CAR T cells to attack cancer cells without any hindrance.”

“When symptoms of CRS begin to manifest, we introduce another molecule—polyethylene glycol (PEG)—to create the suit of armor, which effectively blocks dangerous interactions between these engineered T cells, macrophages, and the tumor cells themselves,” Gong says.

Read the full story in Penn Today.

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Carl June on the Boundless Potential of CAR T Cell Therapy

by Meagan Raeke

Carl June, at the flash mob celebration of the FDA approval of the CAR T cell therapy he developed, in August 2017. (Image: Courtesy of Penn Medicine Magazine)

For most of modern medicine, cancer drugs have been developed the same way: by designing molecules to treat diseased cells. With the advent of immunotherapy, that changed. For the first time, scientists engineered patients’ own immune systems to recognize and attack diseased cells.

One of the best examples of this pioneering type of medicine is CAR T cell therapy. Invented in the Perelman School of Medicine by Carl June, the Richard W. Vague Professor in Immunotherapy, CAR T cell therapy works by collecting T cells from a patient, modifying those cells in the lab so that they are designed to destroy cancerous cells, and reinfusing them into the patient. June’s research led to the first FDA approval for this type of therapy, in 2017. Six different CAR T cell therapies are now approved to treat various types of blood cancers. Carl June, at the flash mob celebration of the FDA approval of the CAR T cell therapy he developed, in August 2017. (Image: Courtesy of Penn Medicine Magazine)

CAR T cell therapy holds the potential to help millions more patients—if it can be successfully translated to other conditions. June and colleagues, including Daniel Baker, a fourth-year doctoral student in the Cell and Molecular Biology department, discuss this potential in a perspective published in Nature.

In the piece, June and Baker highlight other diseases that CAR T cell therapy could be effective.

“CAR T cell therapy has been remarkably successful for blood cancers like leukemias and lymphomas. There’s a lot of work happening here at Penn and elsewhere to push it to other blood cancers and to earlier stage disease, so patients don’t have to go through chemo first,” June says. “Another big priority is patients with solid tumors because they make up the vast majority of cancer patients. Beyond cancer, we’re seeing early signs that CAR T cell therapy could work in autoimmune diseases, like lupus.”

As for which diseases to pursue as for possible future treatment, June says, “essentially it boils down to two questions: Can we identify a population of cells that are bad? And can we target them specifically? Whether that’s asthma or chronic diseases or lupus, if you can find a bad population of cells and get rid of them, then CAR T cells could be therapeutic in that context.”

“What’s exciting is it’s not just theoretical at this point. There have been clinical reports in other autoimmune diseases, including myasthenia gravis and inflammatory myopathy,” Baker says. “But we are seeing early evidence that CAR T cell therapy will be successful beyond cancer. And it’s really opening the minds of people in the field to think about how else we could use CAR T. For example, there’s some pioneering work at Penn from the Epstein lab for heart failure. The idea is that you could use CAR T cells to get rid of fibrotic tissue after a cardiac injury, and potentially restore the damage following a heart attack.”

Baker adds, “there’s no question that over the last decade, CAR T cell therapy has revolutionized cancer. I’m hoping to play a role in bringing these next generation therapies to patients and make a real impact over the next decade. I think there’s potential for cell therapy to be a new pillar of medicine at large, and not just a new pillar of oncology.”

Read the full story at Penn Medicine Today.