Cynthia Reinhart-King, Cornelius Vanderbilt Professor of Engineering and Professor of Biomedical Engineering at Vanderbilt University, was one of a handful of experts invited to take part in the White House Summit in Biotechnology and Biomanufacturing on September 14, 2022 in Washington, D.C. Reinhart-King and her colleagues gathered to discuss “bio-based solutions to global challenges ranging from food security and climate change to health security and supply chain disruptions.”
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.
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.”
Acollaborative team developed an alginate-based hydrogel system that mimics the viscoelasticity of the natural extracellular matrix in bone marrow. By tweaking the balance between elastic and viscous properties in these artificial ECMs, they could recapitulate the viscoelasticity of healthy and scarred fibrotic bone marrow, and study the effects on human monocytes placed into these artificial ECMs. (Image: Adam Graham/Harvard CNS/Wyss Institute at Harvard University)
Fibrosis is the thickening of various tissues caused by the deposition of fibrillar extracellular matrix (ECM) in tissues and organs as part of the body’s wound healing response to various forms of damage. When accompanied by chronic inflammation, fibrosis can go into overdrive and produce excess scar tissue that can no longer be degraded. This process causes many diseases in multiple organs, including lung fibrosis induced by smoking or asbestos, liver fibrosis induced by alcohol abuse, and heart fibrosis often following heart attacks. Fibrosis can also occur in the bone marrow, the spongy tissue inside some bones that houses blood-producing hematopoietic stem cells (HSCs) and can lead to scarring and the disruption of normal functions.
Chronic blood cancers known as “myeloproliferative neoplasms” (MPNs) are one example, in which patients can develop fibrotic bone marrow, or myelofibrosis, that disrupts the normal production of blood cells. Monocytes, a type of white blood cell belonging to the group of myeloid cells, are overproduced from HSCs in neoplasms and contribute to the inflammation in the bone marrow environment, or niche. However, how the fibrotic bone marrow niche itself impacts the function of monocytes and inflammation in the bone marrow was unknown.
Now, a collaborative team from Penn, Harvard, the Dana-Farber Cancer Institute (DFCI), and Brigham and Women’s Hospital has created a programmable hydrogel-based in vitro model mimicking healthy and fibrotic human bone marrow. Combining this system with mouse in vivo models of myelofibrosis, the researchers demonstrated that monocytes decide whether to enter a pro-inflammatory state and go on to differentiate into inflammatory dendritic cells based on specific mechanical properties of the bone marrow niche with its densely packed ECM molecules. Importantly, the team found a drug that could tone down these pathological mechanical effects on monocytes, reducing their numbers as well as the numbers of inflammatory myeloid cells in mice with myelofibrosis. The findings are published in Nature Materials.
“We found that stiff and more elastic slow-relaxing artificial ECMs induced immature monocytes to differentiate into monocytes with a pro-inflammatory program strongly resembling that of monocytes in myelofibrosis patients, and the monocytes to differentiate further into inflammatory dendritic cells,” says co-first author Kyle Vining, who recently joined Penn’s School of Dental Medicine and School of Engineering and Applied Science as an assistant professor of preventive and restorative sciences. “More viscous fast-relaxing artificial ECMs suppressed this myelofibrosis-like effect on monocytes. This opened up the possibility of a mechanical checkpoint that could be disrupted in myelofibrotic bone marrow and also may be at play in other fibrotic diseases.”
Vining worked on the study as a postdoctoral fellow at Harvard in the lab of David Mooney. “Our study shows that the differentiation state of monocytes, which are key players in the immune system, is highly regulated by mechanical changes in the ECM they encounter,” says Mooney, who co-led the study with DFCI researcher Kai Wucherpfennig. “Specifically, the ECM’s viscoelasticity has been a historically under-appreciated aspect of its mechanical properties that we find correlates strongly between our in vitro and the in vivo models and human disease. It turns out that myelofibrosis is a mechano-related disease that could be treated by interfering with the mechanical signaling in bone marrow cells.”
Buffone got his Ph.D. in Chemical Engineering from SUNY Buffalo in Buffalo, NY in 2012, working with advisor Sriram Neelamegham, Professor of Chemical and Biological Engineering. Buffone completed previous postdoctoral studies at Roswell Park Comprehensive Cancer Center with Joseph T.Y. Lau, Distinguished Professor of Oncology in the department of Cellular and Molecular Biology. Upon coming to Penn in 2015, Buffone has worked in the Hammer Lab under advisor Daniel A. Hammer, Alfred G. and Meta A. Ennis Professor in Bioengineering and in Chemical and Biomolecular Engineering, first as a postdoc and later a research associate. Buffone also spent a year as a Visiting Scholar in the Center for Bioengineering and Tissue Regeneration, directed by Valerie M. Weaver, Professor at the University of California, San Francisco in 2019.
While at Penn, Buffone was a co-investigator on an R21 grant through the National Institutes of Health (NIH) which supported his time as a research associate. Buffone is excited to start his own laboratory where he plans to train a diverse set of trainees.
Buffone’s research area lies at the intersection of genetic engineering, immunology, and glycobiology and addresses how to specifically tailor the trafficking and response of immune cells to inflammation and various diseases. The work seeks to identify and subsequently modify critical cell surface and intracellular signaling molecules governing the recruitment of various blood cell types to distal sites. The ultimate goal of his research is to tailor and personalize the innate and adaptive immune response to specific diseases on demand.
“None of this would have been possible without the unwavering support of all of my mentors, past and present, and most especially Dan Hammer,” Buffone says. “His support in helping me transition into an independent scientist and his understanding of my outside responsibilities as a dad with two young children is truly the reason why I am standing here today. It’s a testament to Dan as both a person and a mentor.”
A Philadelphia life sciences company spun out of Penn is emerging from stealth mode with nearly $10 million from a seed funding round. Vittoria Biotherapeutics’ mission is to overcome limitations of CAR T cell therapy by using unique cell engineering and gene editing technologies to create new therapies that address unmet clinical needs. The technology the company is attempting to commercialize was developed by Marco Ruella, M.D., Assistant Professor of Medicine in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group, who is the company’s scientific founder.
The U.S. Food and Drug Administration has expanded its approval for Kymriah, a personalized cellular therapy developed at the Abramson Cancer Center, this time for the treatment of adults with relapsed/refractory follicular lymphoma who have received at least two lines of systemic therapy. “Patients with follicular lymphoma who relapse or don’t respond to treatment have a poor prognosis and may face a series of treatment options without a meaningful, lasting response,” said Stephen J. Schuster, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma in the Division of Hematology Oncology. It’s the third FDAapproval for the “living drug,” which was the first of its kind to be approved, in 2017, and remains the only CAR T cell therapy approved for both adult and pediatric patients.
“In just over a decade, we have moved from treating the very first patients with CAR T cell therapy and seeing them live healthy lives beyond cancer to having three FDA-approved uses of these living drugs which have helped thousands of patients across the globe,” said Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine in Penn’s Perelman School of Medicine and director of the Center for Cellular Immunotherapies in the Abramson Cancer Center and director of the Parker Institute for Cancer Immunotherapy at Penn. “Today’s news is new fuel for our work to define the future of cell therapy and set new standards in harnessing the immune system to treat cancer.”
Research from June, a member of the Penn Bioengineering Graduate Group, led to the initial 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.
Congratulations to the two Bioengineering students to receive 2022 National Science Foundation Graduate Research Fellowship Program (NSF GRFP) fellowships. The prestigious NSF GRFP program recognizes and supports outstanding graduate students in NSF-supported fields. The eighteen Penn 2022 honorees were selected from a highly-competitive pool of over 12,000 applications nationwide. Further information about the program can be found on the NSF website.
Gianna Therese Busch, PhD student, Bioengineering
Gianna is a member of the systems biology lab of Arjun Raj, Professor in Bioengineering and Genetics. Her research focuses on single-cell differences in cancer metabolism and drug resistance.
Shawn Kang, BSE/MSE, Bioengineering (’22)
Shawn conducted research in the BIOLines Lab of Dan Huh, Associate Professor in Bioengineering, where he worked to develop more physiologically relevant models of human health and disease by combining organs-on-a-chip and organoid technology.
The following Bioengineering students also received Honorable Mentions: Michael Steven DiStefano, PhD student Rohan Dipak Patel, PhD student Abraham Joseph Waldman, PhD student
One of the reasons that cancer is notoriously difficult to treat is that it can look very different for each patient. As a result, most targeted therapies only work for a fraction of cancer patients. In many cases, patients will have tumors with no known markers that can be targeted, creating an incredible challenge in identifying effective treatments. A new study seeks to address this problem with the development of a simple methodology to help differentiate tumors from healthy, normal tissues.
This new study, published inScience Advances, was led by Andrew Tsourkas, Professor in Bioengineering and Co-Director of the Center for Targeted Therapeutics and Translational Nanomedicine (CT3N), who had what he describes as a “crazy idea” to use a patient’s antibodies to find and treat their own tumors, taking advantage of the immune system’s innate ability to identify tumors as foreign. This study, spearheaded by Burcin Altun, a former postdoctoral researcher in Tsourkas’s lab, and continued and completed by Fabiana Zappala, a former graduate student in Penn Bioengineering, details their new method for site-specifically labeling “off-the-shelf” and native serum autoantibodies with T cell–redirecting domains.
Researchers have known for some time that cancer patients will generate an antibody response to their own tumors. These anti-tumor antibodies are quite sophisticated in their ability to specifically identify cancer cells; however, they are not sufficiently potent to confer a therapeutic effect. In this study, Tsourkas’s team converted these antibodies into bispecific antibodies, thereby increasing their potency. T cell-redirecting bispecific antibodies are a new form of targeted therapeutic that forms a bridge between tumor cells and T cells which have been found to be as much as a thousand-times more potent than antibodies alone. By combining the specificity of a patient’s own antibodies with the potency of bispecific antibodies, researchers can effectively create a truly personalized therapeutic that is effective against tumors.
In order to test out this new targeted therapeutic approach, the Tsourkas lab had to develop an entirely new technology, allowing them to precisely label antibodies with T cell targeting domains, creating a highly homogeneous product. Previously it has not been possible to convert native antibodies into bispecific antibodies, but Tsourkas’s Targeted Imaging Therapeutics and Nanomedicine or TITAN lab specializes in the creation of novel targeted imaging and therapeutic agents for detection and treatment of various diseases. “Much is yet to be done before this could be considered a practical clinical approach,” says Tsourkas. “But I hope at the very least this works stimulates new ideas in the way we think about personalized medicine.”
In their next phase, Tsourkas’s team will be working to separate anti-tumor antibodies from other antibodies found in patients’ serum (which could potentially redirect the bispecific antibodies to other locations in the body), as well as examining possible adverse reactions or unintended effects and immunogenicity caused by the treatment. However, this study is just the beginning of a promising new targeted therapeutic approach to cancer treatment.
This work was supported by Emerson Collective and the National Institutes of Health, National Cancer Institute (R01 CA241661).
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.
Shawn Kang, BSE/MSE, Bioengineering (’22)
