A new feature in Chemistry World explores the history of CAR (chimeric antigen receptor)-T cell therapy, a revolutionary type of therapeutic treatment for certain types of cancer. One of the pioneers of CAR-T cell therapy is Carl June, Richard W. Vague Professor in Immunotherapy in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group. His groundbreaking research opened the door for FDA approval of the CAR T therapy called Kymriah, which treats acute lymphoblastic leukemia (ALL), one of the most common childhood cancers.
Congratulations to recent Penn Bioengineering graduate Jason Andrechak on winning a Graduate Leadership Awards for 2022. Each year a select number of students across the university are recognized for their service and lasting contributions to graduate student life at Penn. Andrechak, one of only ten recipients in 2022, won a Dr. Andy Binns Award for Outstanding Service to Graduate and Professional Student Life. This award is presented to “graduate or professional students, upon their graduation from Penn, who have significantly impacted graduate and professional student life through service involvement in student life initiatives or organizations.” Andrechak won this award for his “service and leadership in advocating for equity and accessibility during the transition to virtual operations and following a period of leadership transition within the Graduate and Professional Student Assembly (GAPSA). ”
Andrechak completed his Ph.D. in Bioengineering in 2022, where he studied macrophage immunotherapy in solid tumors in the lab of Dennis E. Discher, Robert D. Bent Professor in Chemical and Biomolecular Engineering, Bioengineering, and Mechanical Engineering and Applied Mechanics. He was named a National Science Foundation Graduate Research Fellow in 2018. He has actively led the Graduate Association of Bioengineers (GABE) as Community Service & Outreach chair from 2017-2019 and as co-President from 2019-2022. He also served as the Director of Equity & Access for the Graduate & Professional Student Assembly (GAPSA) from 2020-2021, in addition to several other service and advisory roles at the department, school, and university levels.
Learn more about the Penn Graduate Leadership Awards and read the full list of recipients on the Grad Center at Penn website.
Bill Ludwig, left, was the first patient to receive CAR T cells as part of clinical trials at Abramson Cancer Center. Carl June, right, has played a pioneering roll in the therapeutic use of CAR T cells. (Image: Penn Medicine)
Carl H. June, the Richard W. Vague Professor in Immunotherapy in Pathology and Laboratory Medicine at Penn Medicine, director of the Center for Cellular Immunotherapies and the Parker Institute for Cancer Immunotherapy, and member of the Penn Bioengineering Graduate Group at the University of Pennsylvania, has led a new analytical study published in Nature that explains the longest persistence of CAR T cell therapy recorded to date against chronic lymphocytic leukemia (CLL), and shows that the CAR T cells remained detectable at least a decade after infusion, with sustained remission in both patients. June’s pioneering work in gene therapy led to the FDA approval for the CAR T therapy (sold by Novartis as Kymriah) for treating leukemia and transforming the fight against cancer. His lab develops new forms of T cell based therapies.
A scanning electron micrograph of a healthy human T cell. A better understanding the wide variety of antigen receptors that appear on the surfaces of these critical components of the immune system is necessary for improving a new class of therapies. (Credit: NIAID)
Our bodies are equipped with specialized white blood cells that protect us from foreign invaders, such as viruses and bacteria. These T cells identify threats using antigen receptors, proteins expressed on the surface of individual T cells that recognize specific amino acid sequences found in or on those invaders. Once a T cell’s antigen receptors bind to the corresponding antigen, it can directly kill infected cells or call for backup from the rest of the immune system.
We have hundreds of billions of T cells, each with unique receptors that recognize unique antigens, so profiling this T cell antigen specificity is essential in our understanding of the immune response. It is especially critical in developing targeted immunotherapies, which equip T cells with custom antigen receptors that recognize threats they would otherwise miss, such as the body’s own mutated cancer cells.
Jenny Jiang, Ph.D.
Jenny Jiang, Peter and Geri Skirkanich Associate Professor of Innovation in Bioengineering, along with lab members and colleagues at the University of Texas, Austin, recently published a study in Nature Immunology that describes their technology, which simultaneously provides information in four dimensions of T cell profiling. Ke-Yue Ma and Yu-Wan Guo, a former post doc and current graduate student in Jiang’s Penn Engineering lab, respectively, also contributed to this study.
This technology, called TetTCR-SeqHD, is the first to provide such detailed information about single T cells in a high-throughput manner, opening doors for personalized immune diagnostics and immunotherapy development.
There are many pieces of information needed to comprehensively understand the immune response of T cells, and gathering all of these measurements simultaneously has been a challenge in the field. Comprehensive profiling of T cells includes sequencing the antigen receptors, understanding how specific those receptors are in their recognition of invading antigens, and understanding T cell gene and protein expression. Current technologies only screen for one or two of these dimensions due to various constraints.
“Current technologies that measure T cell immune response all have limitations,” says Jiang. “Those that use cultured or engineered T cells cannot tell us about their original phenotype, because once you take a cell out of the body to culture, its gene and protein expression will change. The technologies that address T cell and antigen sequencing with mass spectrometry damage genetic information of the sample. And current technologies that do provide information on antigen specificity use a very expensive binding ligand that can cost more than a thousand dollars per antigen, so it is not feasible if we want to look at hundreds of antigens. There is clearly room for advancement here.”
The TetTCR-SeqHD technology combines Jiang’s previously developed T cell receptor sequencing tool, TetTCR-Seq, described in a Nature Biotechnology paper published in 2018, with the new ability of characterizing both gene and protein expression.
Our body’s natural line of defense against infection and disease, as well as cancer, is our immune system equipped with T cells, a type of white blood cell that determines how we react to foreign substances, or antigens, in the body. While we have an arsenal of T cells to protect us from these various infections, some people lack certain T cells or simply do not have enough to fight off infections, such as the flu or HIV, or defend against the body’s own mutated cancer cells.
Understanding the diversity of T cells and which antigens they target can provide insight into developing personalized immunotherapy to help those patients with weak spots or gaps in their T cell community. Jenny Jiang, Peter and Geri Skirkanich Associate Professor of Innovation in Bioengineering, is characterizing this diversity.
Jiang recently received a Cancer Research Institute’s (CRI) Lloyd J. Old STAR grant to support her research on this topic. The CRI STAR grant identifies mid-career “Scientists TAking Risks” in innovative cancer immunotherapy research areas, providing freedom and flexibility to pursue high-risk, high-reward research with financial support of $1.25 Million over the course of five years.
Jiang spoke with CRI science writer Arthur Brodsky about her research and how the STAR grant will support it.
“In our studies of healthy individuals, who have some natural immune protection against commonly encountered viruses like the flu, we noticed that not everyone has T cells that cover all the possible antigens,” says Jiang. “There are differences in the number and types of flu-targeting T cells that each individual has. For some “exotic” antigens, like those of HIV for example, although the general population doesn’t actually have exposure to them, they should still have a very low level of minimum T cells that can offer some protection from possible future infection. So that part of our T cell arsenal acts as a safety net. But some individuals may completely lack those T cells. In those cases, as you can imagine, those people will have a hard time overcoming a future infection.”
Jiang describes how this is similar to how our bodies prevent cancerous tumor growth.
Dani S. Bassett, J. Peter Skirkanich Professor in Bioengineering and in Electrical and Systems Engineering
Bassett runs the Complex Systems lab which tackles problems at the intersection of science, engineering, and medicine using systems-level approaches, exploring fields such as curiosity, dynamic networks in neuroscience, and psychiatric disease. They are a pioneer in the emerging field of network science which combines mathematics, physics, biology and systems engineering to better understand how the overall shape of connections between individual neurons influences cognitive traits.
Jason Burdick, Ph.D.
Jason A. Burdick, Robert D. Bent Professor in Bioengineering
Burdick runs the Polymeric Biomaterials Laboratory which develops polymer networks for fundamental and applied studies with biomedical applications with a specific emphasis on tissue regeneration and drug delivery. The specific targets of his research include: scaffolding for cartilage regeneration, controlling stem cell differentiation through material signals, electrospinning and 3D printing for scaffold fabrication, and injectable hydrogels for therapies after a heart attack.
César de la Fuente, Ph.D.
César de la Fuente, Presidential Assistant Professor in Bioengineering and Chemical & Biomedical Engineering in Penn Engineering and in Microbiology and Psychiatry in the Perelman School of Medicine
De la Fuente runs the Machine Biology Group which combines the power of machines and biology to prevent, detect, and treat infectious diseases. He pioneered the development of the first antibiotic designed by a computer with efficacy in animals, designed algorithms for antibiotic discovery, and invented rapid low-cost diagnostics for COVID-19 and other infections.
Carl June, M.D.
Carl H. June, Richard W. Vague Professor in Immunotherapy in the Perelman School of Medicine and member of the Bioengineering Graduate Group
June is the Director for the Center for Cellular Immunotherapies and the Parker Institute for Cancer Therapy and runs the June Lab which develops new forms of T cell based therapies. June’s pioneering research in gene therapy led to the FDA approval for CAR T therapy for treating acute lymphoblastic leukemia (ALL), one of the most common childhood cancers.
Vivek Shenoy, Ph.D.
Vivek Shenoy, Eduardo D. Glandt President’s Distinguished Professor in Bioengineering, Mechanical Engineering and Applied Mechanics (MEAM), and in Materials Science and Engineering (MSE)
Shenoy runs the Theoretical Mechanobiology and Materials Lab which develops theoretical concepts and numerical principles for understanding engineering and biological systems. His analytical methods and multiscale modeling techniques gain insight into a myriad of problems in materials science and biomechanics.
The highly anticipated annual list identifies researchers who demonstrated significant influence in their chosen field or fields through the publication of multiple highly cited papers during the last decade. Their names are drawn from the publications that rank in the top 1% by citations for field and publication year in the Web of Science™ citation index.
Bassett and Burdick were both on the Highly Cited Researchers list in 2019 and 2020.
The methodology that determines the “who’s who” of influential researchers draws on the data and analysis performed by bibliometric experts and data scientists at the Institute for Scientific Information™ at Clarivate. It also uses the tallies to identify the countries and research institutions where these scientific elite are based.
David Pendlebury, Senior Citation Analyst at the Institute for Scientific Information at Clarivate, said: “In the race for knowledge, it is human capital that is fundamental and this list identifies and celebrates exceptional individual researchers who are having a great impact on the research community as measured by the rate at which their work is being cited by others.”
The full 2021 Highly Cited Researchers list and executive summary can be found online here.
Scientific American recently featured two gene therapies that were invented at Penn, including research from Carl June, MD, the Richard W. Vague Professor in Immunotherapy in Pathology and Laboratory Medicine, director of the Center for Cellular Immunotherapies, and member of the Penn Bioengineering Graduate Group, which led to the FDA approval for the CAR T therapy (sold by Novartis as Kymriah) for treating acute lymphoblastic leukemia (ALL), one of the most common childhood cancers.
Speaker: Susan N. Thomas, Ph.D.
Woodruff Associate Professor of Mechanical Engineering
Parker H. Petit Institute of Bioengineering and Bioscience
Georgia Institute of Technology
Date: Thursday, September 23, 2021
Time: 3:30-4:30 PM EDT
Zoom – check email for link or contact ksas@seas.upenn.edu
This virtual seminar will be held over Zoom. Students registered for BE 699 can gather to watch live in Moore 216, 200 S. 33rd Street.
Abstract: Lymph nodes mediate the co-mingling of cells of the adaptive system to coordinate adaptive immune response. Drug delivery principles and technologies our group has developed to leverage the potential of lymph nodes as immunotherapeutic drug targets to augment anti-cancer therapeutic effects will be described.
Susan Thomas Bio: Susan Napier Thomas is a Woodruff Associate Professor with tenure of Mechanical Engineering in the Parker H. Petit Institute of Bioengineering and Bioscience at the Georgia Institute of Technology where she holds adjunct appointments in Biomedical Engineering and Biological Science and is a member of the Winship Cancer Institute of Emory University. Prior to this appointment, she was a Whitaker postdoctoral scholar at École Polytechnique Fédérale de Lausanne and received her B.S. in Chemical Engineering cum laude from the University of California Los Angeles and her Ph.D. as in Chemical & Biomolecular Engineering as an NSF Graduate Research Fellow from The Johns Hopkins University. For her contributions to the emerging field of immunoengineering, she has been honored with the 2018 Young Investigator Award from the Society for Biomaterials for “outstanding achievements in the field of biomaterials research” and the 2013 Rita Schaffer Young Investigator Award from the Biomedical Engineering Society “in recognition of high level of originality and ingenuity in a scientific work in biomedical engineering.” Her interdisciplinary research program is supported by multiple awards from the National Cancer Institute, the Department of Defense, the National Science Foundation, and the Susan G. Komen Foundation, amongst others.
Jenny Jiang, the Peter & Geri Skirkanich Associate Professor of Innovation in the department of Bioengineering, has received a Lloyd J. Old STAR Program grant from the Cancer Research Institute (CRI), which is a major supporter of cancer immunotherapy research and clinical trials with the goal of curing all types of cancer.
The CRI Lloyd J. Old Scientists Taking Risks (STAR) Program “provides long-term funding to mid-career scientists, giving them the freedom and flexibility to pursue high-risk, high-reward research at the forefront of discovery and innovation in cancer immunotherapy.” This prestigious grant was give to six awardees this year, chosen from a pool of hundreds of applicants, and recognizes “future leaders in the field of cancer immunotherapy [who are expected to] carry out transformational research.”
The Old STAR Program Grant comes with $1.25 million in funding over 5 years to support the awardees’ cancer immunology research.
Jiang, who recently joined Penn Bioengineering, is a pioneer in developing tools in genomics, biophysics, immunology, and informatics and applying them to study systems immunology and immune engineering in human diseases. She was also inducted into the American Institute for Medical and Biological Engineering (AIMBE) College of Fellows in March 2021 for her outstanding contributions to the field of systems immunology and immunoengineering and devotion to the success of women in engineering. Jiang’s research focuses on systems immunology by developing technologies that enable high-throughput, high-content, single cell profiling of T cells in health and disease and she is recognized as one of the leading authorities in systems immunology and immunoengineering.
“The STAR Award from CRI allows my lab to answer some of the fundamental questions in T cell biology, such as is the T cell repertoire complete to cover all possible cancer antigens, as well as to improve the efficacy of T cell based cancer immunotherapies,” says Jiang.
Penn Medicine researchers have developed a unifying definition of ‘cytokine storm’ to provide a framework to assess and treat patients whose immune systems have gone rogue.
Penn Medicine’s David Fajgenbaum (left) and Carl June (right). (Image: Penn Medicine News)
One of the most elusive aspects for clinicians treating COVID-19 is the body’s immune response to the virus. In the most severe cases of COVID-19, the immune system goes into overdrive, resulting in a fever, multiorgan system damage, and often death—a cytokine storm. But how to detect and treat a cytokine storm requires that clinicians can identify it as such.
Two Penn Medicine researchers have developed a unifying definition of “cytokine storm” to provide physicians with a framework to assess and treat severely-ill patients whose immune systems have gone rogue. Cytokine storms can be triggered by different pathogens, disorders, or treatments, from COVID-19 to Castleman disease to CAR T cell therapy.
In a paper published in the New England Journal of Medicine, David Fajgenbaum,an assistant professor of translational medicine & human genetics and director of the Center for Cytokine Storm Treatment & Laboratory (CSTL), and Carl June,a professor of pathology and laboratory medicine and director of the Center for Cellular Immunotherapies in the Abramson Cancer Center, and the Parker Institute for Cancer Immunotherapies define a cytokine storm as requiring elevated circulating cytokine levels, acute systemic inflammatory symptoms, and secondary organ dysfunction beyond what could be attributed to a normal response to a pathogen, if a pathogen is present.
“There has never been a defining central review of what a cytokine storm is and how to treat one, and now with COVID-19, that is a major issue,” says Fajgenbaum, a Castleman disease patient who has previously experienced five cytokine storms himself. “I’ve spent the last 10 years of my life as a cytokine storm patient and researcher, so I know the importance of having a comprehensive unified definition to find therapies that work across the various types of cytokine storms.”
There is widespread recognition that the immune response to a pathogen, but not the pathogen itself, can contribute to multiorgan dysfunction and other symptoms. Additionally, similar cytokine storm syndromes can occur with no obvious infection.
