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.
When it comes to human bodies, there is no such thing as typical. Variation is the rule. In recent years, the biological sciences have increased their focus on exploring the poignant lack of norms between individuals, and medical and pharmaceutical researchers are asking questions about translating insights concerning biological variation into more precise and compassionate care.
What if therapies could be tailored to each patient? What would happen if we could predict an individual body’s response to a drug before trial-and-error treatment? Is it possible to understand the way a person’s disease begins and develops so we can know exactly how to cure it?
An innovator of organ-on-a-chip technology, or miniature copies of bodily systems stored in plastic devices no larger than a thumb drive, Huh has broadened his attention to engineering mini-organs in a dish using a patient’s own cells.
A study published in Nature Biomedical Engineering details a novel method for imaging the placenta in pregnant patients as well as the results of a pilot clinical study. By combining optical measurements with ultrasound, the findings show how oxygen levels can be monitored noninvasively and provides a new way to generate a better understanding of this complex, crucial organ. This research was the result of a collaboration of the groups of the University of Pennsylvania’s Arjun Yodh and Nadav Schwartz with colleagues from the Children’s Hospital of Philadelphia (CHOP) and was led by postdoc Lin Wang.
Schwartz describes the placenta as the “engine” of pregnancy, an organ that plays a crucial role in delivering nutrients and oxygen to the fetus. Placental dysfunction can lead to complications such as fetal growth restriction, preeclampsia, and stillbirth. To increase knowledge about this crucial organ, the National Institute of Child Health and Human Development launched the Human Placenta Project in 2014. One focus of the program is to develop tools to assess human placental structure and function in real time, including optical devices.
For three years, the researchers optimized the design of their instrument and tested it in preclinical settings. The process involved integrating optical fibers with ultrasound probes, exploring various ultrasound transducers, and improving the multimodal technology so that measurements were stable, accurate, and reproducible while collecting data at the bedside. The resulting instrumentation now enables researchers to study the anatomy of the placenta while also collecting detailed functional information about placenta blood flow and oxygenation, capabilities that existing commercially devices do not have, the researchers say.
Because the placenta is located far below the body’s surface, one of the key technical challenges addressed by Wang, a postdoc in Yodh’s lab, was reducing background noise in the opto-electronic system. Light is scattered and absorbed when it travels through thick tissues, Yodh says, and the key for success was to reduce background interference so that the small amount of light that penetrates deep into the placenta and then returns is still large enough for a high-quality measurement.
“We’re sending a light signal that goes through the same deep tissues as the ultrasound. The extremely small amount of light that returns to the surface probe is then used to accurately assess tissue properties, which is only possible with very stable lasers, optics, and detectors,” says Yodh. “Lin had to overcome many barriers to improve the signal-to-noise ratio to the point where we trusted our data.”
The authors are Lin Wang, Jeffrey M. Cochran, Kenneth Abramson, Lian He, Venki Kavuri, Samuel Parry, Arjun G. Yodh, and Nadav Schwartz from Penn; Tiffany Ko, Wesley B. Baker, and Rebecca L. Linn from the Children’s Hospital of Philadelphia, and David R. Busch, previously a research associate at Penn and now at the University of Texas Southwestern Medical School.
Carl June, MD, Professor in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group, was quoted in a recent press release announcing a new international partnership between Penn Medicine (PSOM), the Children’s Hospital of Pennsylvania (CHOP), and Costa Rica’s CCSS, or the Caja Costarricense de Seguro Social (Social Security Program), to develop CAR T research in Costa Rica. June is a world renowned cancer cell therapy pioneer whose research led to the initial development and FDA approval of CAR T cell therapy:
“‘At least 15,000 patients across the world have received CAR T cells, and dozens more clinical trials using this approach are in progress, for almost every major tumor type, but people in many parts of the globe still do not have access to treatment with these transformative therapies,’ said Carl H. June, MD, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies in Penn’s Perelman School of Medicine. “We are honored to work with our colleagues in Costa Rica in hopes of building a path for patients in underserved areas to have the opportunity to benefit from clinical research programs offering this personalized therapy.’”
Kevin B. Johnson, M.D., M.S., was featured in Cincinnati Children’s Hospital’s “Envisioning Our Future for Children” speaker series, discussing “the evolution of the EHR and its future directions.” An electronic health record, or EHR, is a digital record of a patient’s chart, recording health information and data, coordinating orders, tracking results, and providing patient support. Johnson “predicts a new wave of transformation in digital health technologies that could make rapid progress” in several areas of medicine, including reducing cost and improving patience outcomes. Johnson is Vice President for Applied Informatics at the University of Pennsylvania Health System and the David L. Cohen University Professor with appointments in Biostatistics, Epidemiology and Informatics and Computer and Information Science and secondary appointments in the Annenberg School for Communication, Pediatrics, and Bioengineering.
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.
Joseph Lance Casila, a doctoral student and Fontaine Fellow in Bioengineering, was profiled by his alma mater, the University of Guam (UOG. Casila was the first person in his family to graduate from a U.S.-accredited university and is now studying tissue engineering and regenerative medicine in the Bioengineering and Biomaterials Laboratory of Riccardo Gottardi, Assistant Professor in Bioengineering in Penn Engineering and Pediatrics in Penn Medicine and the Children’s Hospital of Philadelphia (CHOP). His research in the Gottardi lab employs “tissue engineering and drug delivery for biomedical problems relating to knees, ears, nose, and throat but specifically to pediatric airway disorders.” The article discusses Casila’s journey from valedictorian of his high school, to a first-generation undergraduate interested bioengineering, and now a graduate student studying at Penn on a full scholarship. After completing his degree, Casila hopes to bring what he’s learned back home to advance health care in Guam.
“My mentors, and especially my friends, helped me make the most of what UOG had to offer, and it paid off rewardingly,” he said. “You get what you put in.”
Endotracheal tubes are a mainstay of hospital care, as they ensure a patient’s airway is clear when they can’t breathe on their own. However, keeping a foreign object inserted in this highly sensitive part of the anatomy comes is not without risk, such as the possibility of infection, inflammation and a condition known as subglottic stenosis, in which scar tissue narrows the airway.
Broad-spectrum antibiotics are one way to mitigate these risks, but come with risks of their own, including harming beneficial bacteria and contributing to antibiotic resistance.
With this conundrum in mind, Riccardo Gottardi, Assistant Professor of Pediatrics at the Children’s Hospital of Philadelphia (CHOP) and of Bioengineering at Penn Engineering, along with Bioengineering graduate students and lab members Matthew Aronson and Paul Gehret, are developing endotracheal tubes that can provide a more targeted antimicrobial defense.
In a proof-of-concept study published in the journal The Laryngoscope, the team showed how a different type of antimicrobial agent could be incorporated into the tubes’ polymer coating, as well as preliminary results suggesting these devices would better preserve a patient’s microbiome.
Instead, the investigators explored the use of antimicrobial peptides (AMPs), which are small proteins that destabilize bacterial membranes, causing bacterial cells to fall apart and die. This mechanism of action allows them to target specific bacteria and makes them unlikely to promote antimicrobial resistance. Prior studies have shown that it is possible to coat endotracheal tubes with conventional antibiotics, so the research team investigated the possibility of incorporating AMPs into polymer-coated tubes to inhibit bacterial growth and modulate the upper-airway microbiome.
The researchers, led by Matthew Aronson, a graduate student in Penn Engineering’s Department of Bioengineering, tested their theory by creating a polymer coating that would release Lasioglossin-III, an AMP with broad-spectrum antibacterial activity. They found that Lasio released from coated endotracheal tubes, reached the expected effective concentration rapidly and continued to release at the same concentration for a week, which is the typical timeframe that an endotracheal is used before being changed. The investigators also tested their drug-eluting tube against airway microbes, including S. epidermidis, S. pneumoniae, and human microbiome samples and observed significant antibacterial activity, as well as prevention of bacterial adherence to the tube.
Read “CHOP Researchers Develop Coating for Endotracheal Tubes that Releases Antimicrobial Peptides” at CHOP News.
Colin Huber, a Ph.D. candidate in Bioengineering studying head impact biomechanics and concussion in sports at the Center for Injury Research and Prevention (CIRP) at the Children’s Hospital of Philadelphia (CHOP), recently published “Variations in Head Impact Rates in Male and Female High School Soccer” in Medicine & Science in Sports & Exercise with colleagues from CHOP’s Minds Matter Concussion Frontier Program and the CIRP.
Colin’s paper, the goal of which was to compare “to compare head impact exposure rates (head impacts/exposure period) in male and female high school soccer by using multiple methodological approaches,” was recently profiled in the Penn Engineering Research & Innovation Newsletter.
Researchers from Penn and CHOP detail the mechanism by which HIV infection blocks the maturation process of brain cells that produce myelin, a fatty substance that insulates neurons.
It’s long been known that people living with HIV experience a loss of white matter in their brains. As opposed to gray matter, which is composed of the cell bodies of neurons, white matter is made up of a fatty substance called myelin that coats neurons, offering protection and helping them transmit signals quickly and efficiently. A reduction in white matter is associated with motor and cognitive impairment.
In a new study using both human and rodent cells, the team has hammered out a detailed mechanism, revealing how HIV prevents the myelin-making brain cells called oligodendrocytes from maturing, thus putting a wrench in white matter production. When the researchers applied a compound blocking this process, the cells were once again able to mature.
“Even when people with HIV have their disease well-controlled by antiretrovirals, they still have the virus present in their bodies, so this study came out of our interest in understanding how HIV infection itself affects white matter,” says Kelly Jordan-Sciutto, a professor in Penn’s School of Dental Medicine and co-senior author on the study. “By understanding those mechanisms, we can take the next step to protect people with HIV infection from these impacts.”
“When people think about the brain, they think of neurons, but they often don’t think about white matter, as important as it is,” says Judith Grinspan, a research scientist at CHOP and the study’s other co-senior author. “But it’s clear that myelination is playing key roles in various stages of life: in infancy, in adolescence, and likely during learning in adulthood too. The more we find out about this biology, the more we can do to prevent white matter loss and the harms that can cause.”
Jordan-Sciutto and Grinspan have been collaborating for several years to elucidate how ART and HIV affect the brain, and specifically oligodendrocytes, a focus of Grinspan’s research. Their previous work on antiretrovirals had shown that commonly used drugs disrupted the function of oligodendrocytes, reducing myelin formation.
In the current study, they aimed to isolate the effect of HIV on this process. Led by Lindsay Roth, who recently earned her doctoral degree within the Biomedical Graduate Studies group at Penn and completed a postdoctoral fellowship working with Jordan-Sciutto and Grinspan, the investigation began by looking at human macrophages, one of the major cell types that HIV infects.
Kelly Jordan-Sciutto is vice chair and professor in the University of Pennsylvania School of Dental Medicine’s Department of Basic & Translational Sciences and is director of Biomedical Graduate Studies. She is a member of the Penn Bioengineering Graduate Group.