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.
The Solomon R. Pollack Award for Excellence in Graduate Bioengineering Research is given annually to the most deserving Bioengineering graduate students who have successfully completed research that is original and recognized as being at the forefront of their field. This year, the Department of Bioengineering at the University of Pennsylvania recognizes the stellar work of four graduate students in Bioengineering.
Dissertation: “Ionizable Lipid Nanoparticles for mRNA CAR T Cell Engineering”
Margaret earned a bachelor’s degree in Biomedical Engineering from the University of Delaware where she conducted research in the Day Lab on the use of antibody-coated gold nanoparticles for the detection of circulating tumor cells. She conducted doctoral research in the lab of Michael J. Mitchell, J. and Peter Skirkanich Assistant Professor in Bioengineering. After defending her thesis at Penn in 2022, Margaret began postdoctoral training at the Massachusetts Institute of Technology (MIT) in the Hammond Lab where she is investigating the design and application of polymeric nanoparticles for combination therapies in ovarian cancer. She plans to use these experiences to continue a research career focused on drug delivery systems.
“Maggie was an absolutely prolific Ph.D. student in my lab, who pioneered the development of new mRNA lipid nanoparticle technology to engineer the immune system to target and kill tumor cells,” says Mitchell. “Maggie is incredibly well deserving of this honor, and I am so excited to see what she accomplishes next as a Postdoctoral Fellow at MIT and ultimately as a professor running her own independent laboratory at a top academic institution.”
Dissertation: “Designing Hyaluronic Acid Granular Hydrogels for Biomaterials Applications”
Victoria is currently a Princeton University Presidential Postdoctoral Research Fellow in the lab of Sujit S. Datta, where she studies microbial community behavior in 3D environments. She obtained her Ph.D. in 2022 as an NSF Graduate Research Fellow at Penn Bioengineering under the advisement of Jason A. Burdick, Adjunct Professor in Bioengineering at Penn and Bowman Endowed Professor in Chemical and Biological Engineering at the University of Colorado, Boulder. She received a B.ChE. in Chemical Engineering from the University of Delaware in 2018 as a Eugene DuPont Scholar. Outside of research, Victoria is highly active in volunteer and leadership roles within the American Institute of Chemical Engineers (AIChE), currently serving as Past Chair of the Young Professionals Community and a member of the Career and Education Operating Council (CEOC). Victoria’s career aspiration is to become a professor of chemical engineering and to lead a research program at the interaction of biomaterials, soft matter, and microbiology.
“Victoria was a fantastic Ph.D. student,” says Burdick. “She worked on important projects related to granular materials from the fundamentals to applications in tissue repair. She was also a leader in outreach activities, a great mentor to numerous undergraduates, and is already interviewing towards an independent academic position.”
Dissertation: “Characterizing Medial Temporal Lobe Neurodegeneration Due to Tau Pathology in Alzheimer’s Disease Using Postmortem Imaging”
Sadhana completed her B.S. in Electrical Engineering at the University of Cape Town, South Africa in 2014 and her M.S. in Biomedical Engineering from Carnegie Mellon University in 2017. Outside of the lab, she enjoys spending time in nature and exploring restaurants in Philadelphia with friends. She focused her doctoral work on the development of computational image analysis techniques applied to ex vivo human brain imaging data in the Penn Image Computing and Science Laboratory of Paul Yushkevich, Professor of Radiology at the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group. She hopes to continue working at the intersection of machine learning and biomedical imaging to advance personalized healthcare and drug development.
“Dr. Sadhana Ravikumar’s Ph.D. work is a tour de force that combines novel methodological contributions crafted to address the challenge of anatomical variability in ultra-high resolution ex vivo human brain MRI with new clinical knowledge on the contributions of molecular pathology to neurodegeneration in Alzheimer’s disease,” says Yushkevich. “I am thrilled that this excellent contribution, as well as Sadhana’s professionalism and commitment to mentorship, have been recognized through the Sol Pollack award.”
Dissertation: “Remote Force Guided Assembly of Complex Orthopaedic Tissues”
Hannah was a Ph.D. candidate in the lab of Robert Mauck, Mary Black Ralston Professor in Orthopaedic Surgery and in Bioengineering. She successfully defended her thesis and graduated in August 2022. During her Ph.D., Hannah advanced the state-of-the-art in articular cartilage repair by harnessing remote fields, such as magnetism and gravity. Using these non-invasive forces, she was able to control cell positioning within engineered tissues, similar to the cell patterns within native cartilage, and enhance the integration between cartilage and bone. Her work could be used in many tissue engineering applications to recreate complex tissues and tissue interfaces. Hannah earned a B.S. in Biological Engineering from the Massachusetts Institute of Technology (MIT) in 2017 during which time she was also a member of the women’s varsity soccer team. At Penn, Hannah was also involved in the Graduate Association of Bioengineers (GABE) intramurals & leadership, and helped jumpstart the McKay DEI committee. Since completing her Ph.D., Hannah has begun her postdoctoral research as a Schmidt Science Fellow in Jason Burdick’s lab at the University of Colorado Boulder where she looks to improve in vitro disease models for osteoarthritis.
“Hannah was an outstanding graduate student, embodying all that is amazing about Penn BE – smart, driven, inventive and outstanding in every way,” says Mauck. “ I can’t wait to see where she goes and what she accomplishes!”
Congratulations to our four amazing 2023 Sol Pollack Award winners!
Congratulations to two Bioengineering graduate students who were awarded Student Travel Achievement Recognition (STAR) Awards from the Society for Biomaterials (SFB). The STAR Award recognizes research excellence and develops future leaders within SFB and comes with a certificate and a monetary award of $250. Penn Bioengineering graduate students Rebecca Haley and Alex Hamilton, both members of the lab of Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in Bioengineering, received their awards and presented on their research in the SFB annual meeting in April 2023.
Rebecca Haley is a Ph.D. student in Bioengineering and a NSF Graduate Research Fellow. In the Mitchell Lab, she focuses on the use of ionizable lipid nanoparticles for the delivery of protein cargos. Supported by this STAR award, she presented her work delivering small protein RAS-inhibitors that reduce cancer cell proliferation. Rebecca is interested in expanding the applications of lipid nanoparticle technology, allowing currently limited therapeutics to achieve functional delivery and, hopefully, clinical success.
Alex Hamilton is a Ph.D. student in Bioengineering and an NSF Graduate Research Fellow. Alex’s work in the Mitchell lab focuses on non-viral nucleic acid delivery. His research interests include cancer immunotherapy, vaccines, and fetal-maternal medicine. He is currently engaged in using novel high-throughput screening techniques to accelerate the discovery process for lipid nanoparticle development for a variety of disease applications.
Two more Mitchell Lab members were likewise recognized with honorable mention inn the STAR Awards: Hannah Safford, a Ph.D. student in Bioengineering and NSF Fellow, and Rohan Palanki, a M.D.-Ph.D. student in Bioengineering and NIH Fellow
Learn more about the Mitchell Lab’s research in biomaterials science, drug delivery, and cellular and molecular bioengineering in the lab’s website.
Read more stories featuring Mitchell and his team here.
Ten winners of the 2023 Penn Prize for Excellence in Teaching by Graduate Students were announced at a ceremony held April 13 at the Graduate Student Center. The recipients, who represented five of Penn’s 12 schools, were recognized among a pool of 44 Ph.D. candidates and master’s students nominated primarily by undergraduates—a quality unique to and cherished about this Prize.
“It’s a particularly authentic expression of gratitude from undergraduates, and that’s really the pleasure [of presenting these awards],” says Vice Provost for Education Karen Detlefsen, who was present to announce the winners and award them with a certificate. (They also receive a monetary award.) “I’m so proud of our students: Our undergraduates, for taking the time to recognize what it is our graduate students contribute to the student body, and the graduate students who are contributing to the life of the University.
“Students are the lifeblood of the University and without them, we wouldn’t be here.”
The Prize began in the 1999-2000 academic year under former Penn President Judith Rodin. It was spearheaded by then-doctoral-candidate Eric Eisenstein and has been issued every year since. Nominations for the Prize often mention how graduate teaching assistants were able to take a complex subject and make it relatable or craft a course like philosophy or mathematics into an enjoyable—even highly anticipated—experience for students.
“Many nominations show how much students value a TA or a graduate instructor of record who shows that they care for their learning and for them as people, and who makes themself readily available to assist,” says Ian Petrie, director of graduate student programming for the Center for Teaching and Learning, who organizes the selection committee for the Prize. “Typically, however, committee members are also interested in seeing nominations that really point to how a graduate student instructor taught or gave feedback—not just how responsive they were to emails or how many office hours they had.”
He also emphasizes that many winners this year were not just teachers, but mentors—often helping undergraduates or new graduate students navigate not only the course but also Penn as an institution.
Guruprasad studies mechanisms of resistance to chimeric antigen receptor (CAR) T cell therapy for cancer. He has served as a teaching assistant for five semesters: three for Intro to Biotransport Processes (BE 3500) taught by Alex Hughes, Assistant Professor in Bioengineering, and two for Cellular Engineering (BE 3060), taught by Daniel Hammer, Alfred G. and Meta A. Ennis Professor in Bioengineering and in Chemical and Biomolecular Engineering. Both courses are a part of the core curriculum for undergraduate bioengineering students. His doctoral thesis focuses on how a specific interaction between CAR T cells and tumor cells limits their function across a range of cancers.
“I make myself approachable outside the classroom, and I think that’s one aspect of being a TA: having responsibilities that extend beyond the classroom,” says Guruprasad. “Dozens of times, I’ve spoken to students over coffee, or over some lunch, about what direction they want to take in their life, what they want to do outside of the course, and give them my two cents of advice. I try to individualize.”
This post was adapted from an original story by Brandon Baker in Penn Today. Read the full story and list of 2023 winners here.
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.
Up to 50 percent of cancer-signaling proteins once believed to be immune to drug treatments due to a lack of targetable protein regions may actually be treatable, according to a new study from the Perelman School of Medicine at the University of Pennsylvania. The findings, published this month in Nature Communications, suggest there may be new opportunities to treat cancer with new or existing drugs.
Researchers, clinicians, and pharmacologists looking to identify new ways to treat medical conditions—from cancer to autoimmune diseases—often focus on protein pockets, areas within protein structures to which certain proteins or molecules can bind. While some pockets are easily identifiable within a protein structure, others are not. Those hidden pockets, referred to as cryptic pockets, can provide new opportunities for drugs to bind to. The more pockets scientists and clinicians have to target with drugs, the more opportunities they have to control disease.
The research team identified new pockets using a Penn-designed neural network, called PocketMiner, which is artificial intelligence that predicts where cryptic pockets are likely to form from a single protein structure and learns from itself. Using PocketMiner—which was trained on simulations run on the world’s largest super computer—researchers simulated single protein structures and successfully predicted the locations of cryptic pockets in 35 cancer-related protein structures in thousands of areas of the body. These once-hidden targets, now identified, open up new approaches for potentially treating existing cancer.
What’s more, while successfully predicting the cryptic pockets, the method scientists used in this study was much faster than previous simulation or machine-learning methods. The network allows researchers to nearly instantaneously decide if a protein is likely to have cryptic pockets before investing in more expensive simulations or experiments to pursue a predicted pocket further.
“More than half of human proteins are considered undruggable due to an apparent lack of binding proteins in the snapshots we have,” said Gregory R. Bowman, PhD, a professor of Biochemistry and Biophysics and Bioengineering at Penn and the lead author of the study. “This PocketMiner research and other research like it not only predict druggable pockets in critical protein structures related to cancer but suggest most human proteins likely have druggable pockets, too. It’s a finding that offers hope to those with currently untreatable diseases.”
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
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.
“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.”
In many instances, the physical manifestation of cancers and the ways they are subsequently diagnosed is via a tumor, tissue masses of mutated cells and structures that grow excessively. One of the major mysteries in understanding what goes awry in cancers relates to the environments within which these structures grow, commonly known as the tumor microenvironment.
These microenvironments play a role in facilitating tumor survival, growth, and spread. Tumors can help generate their own infrastructure in the form of vasculature, immune cells, signaling molecules, and extracellular matrices (ECMs), three-dimensional networks of collagen-rich support scaffolding for a cell. ECMs also help regulate cellular communications, and in the tumor microenvironment ECMs can be a key promoter of tumor growth by providing structural support for cancerous cells and in modulating signaling pathways that promote growth.
Now, new research led by the School of Arts & Science’sWei Guo and published in the journal Nature Cell Biology has bridged the complex structural interactions within the tumor microenvironment to the signals that trigger tumor growth. The researchers studied cancerous liver cells grown on ECMs of varying stiffness and discovered that the stiffening associated with tumor growth can initiate a cascade that increases the production of small lipid-encapsulated vesicles known as exosomes.
“By recording the number of packages sent, the addresses on these packages, their contents, and most importantly, how they’re regulated and generated, we can better understand the relationship between a patient’s tumor microenvironment and their unique molecular signaling signatures, hinting at more robust personalized cancer therapies,” Radhakrishnan says.
While studying exosomes in relation to tumor growth and metastasis has been well-documented in recent years, researchers have mostly focused on cataloging their characteristics rather than investigating the many processes that govern the creation and shuttling of exosomes between cells. As members of Penn’s Physical Sciences Oncology Center (PSOC), Guo and Radhakrishnan have long collaborated on projects concerning tissue stiffness. For this paper, they sought to elucidate how stiffening promotes exosome trafficking in cancerous intracellular signaling.
“Our lab previously found that high stiffness promotes the secretion of exosomes,” says Di-Ao Liu, co-first author of the paper and a graduate student in the Guo Lab. “Now, we were able to model the stiffening processes through experiments and identify molecular pathways and protein networks that cause this, which better links ECM stiffening to cancerous signaling.”
Perelman School of Medicine (PSOM) professors and Penn Bioengineering Graduate Group members Carl June and Avery Posey are leading the charge in T cell therapy and the fight against cancer.
Advances in genome editing through processes such as CRISPR, and the ability to rewire cells through synthetic biology, have led to increasingly elaborate approaches for modifying and supercharging T cells for therapy. Avery Posey, Assistant Professor of Pharmacology, and Carl June, the Richard W. Vague Professor in Immunotherapy, explain how new techniques are providing tools to counter some of the limitations of current CAR T cell therapies in a recent Nature feature.
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 Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in Bioengineering.
Solid tumors evade the immune system’s ability to attack them in part due to the tumors’ tough, fibrous biological barriers that circulating immune cells can’t cross. Researchers need to identify ways to deliver individualized treatments that can better target these tumors without causing damage to healthy tissues or affecting overall quality of life.
The Status Quo
Current cancer treatments typically involve surgery, radiation or chemo- therapy to eliminate solid tumors. These treatments are invasive and can cause numerous negative downstream effects. Newer treatments involve engineering a patient’s immune system to recognize and fight cancerous cells, but are so far only effective against certain “liquid” cancers, where the mutated cells circulate freely in the blood and bone marrow and are small enough to be picked off by the patient’s upgraded T cells. Additionally, existing methods can also require that the cell engineering take place in a lab rather than directly inside the body.
The Mitchell Lab’s Fix
Members of the lab of Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in Bioengineering, are looking to utilize nanoparticle delivery technology developed by their lab to engineer a different type of immune cell, the macrophage, in order to fight solid- tumor cancers from the inside.
The Mitchell lab is using lipid nanoparticles (LNPs) to carry mRNA and DNA sequences inside of macrophages, a type of immune cell that can consume tumor cells if engineered correctly. In theory, a patient would receive an injection carrying the LNP payload, and the macrophages, whose name literally means “big eaters,” would take up the genetic sequence, alter their function and be able to recognize a patient’s own unique tumor cells in the body.
Because of the way macrophages operate, they could cross the tumor’s biological barrier and attack the cells, destroying the tumor from the inside. An added benefit of the Mitchell Lab’s technology is that the destroyed tumor cells would then also allow other immune cells to present their antigens to circulating T cells, which could then learn to fight those same cancer cells in the future.
“One of the longstanding challenges that we face in the context of cancer and immunotherapies is that every tumor has unique antigens that are specific to patients,” says Mitchell. “This is why we’ve had a lot of trouble developing targeted therapies. Personalizing an approach by harnessing an individual’s immune system gives each patient a greater chance of a positive outcome.”