Making what’s next in medicine: Why research at Penn powers many FDA-approved treatments

The news reached Abramson Cancer Center (ACC) Director Robert Vonderheide, MD, DPhil, at 11 a.m. on August 30, 2017. It was official: That morning, the U.S. Food and Drug Administration (FDA) approved a Penn Medicine-developed personalized cellular immune therapy.

Six hours later, Vonderheide was standing atop a coffee counter in the atrium of the Perelman Center for Advanced Medicine, addressing hundreds of jubilant faculty and staff members who had gathered for a now-iconic "flash mob" celebration of the milestone. Carl June, MD, and a team of scientists, physicians, and other dedicated staff had together turned a dream of using patients’ own immune cells to treat their cancer, into a reality.

Vonderheide called the discovery “a 20-year overnight sensation.” It would be a defining moment for Penn’s identity as a place that incubates and brings to life some of the most transformative modern medical advancements.

The FDA approval of chimeric antigen receptor (CAR) T cell therapy didn’t happen at Penn Medicine by chance. Nor did the others that followed. Since that day, other medical innovations and research that had been underway at Penn Medicine directly influenced at least two dozen more FDA approvals granted to cancer drugs and other medical technologies—giving the stamp of safety and effectiveness needed for these treatments to be widely available to patients outside of clinical trials. Eleven of the medical advancements documented to date represent the first FDA approvals in their classes: eight under cancer, two under gene therapy, and the revolutionary mRNA technology that powers COVID-19 vaccines around the world.

Penn Medicine faculty may lead this crucial work at different points across the continuum of discovery, from conducting pivotal discovery science in the lab which leads to licensing of compounds and technologies by commercial partners, to leading clinical trials of new therapies initially developed outside of Penn.

The list of Penn-linked FDA approvals is growing with each passing year, and for good reason. Science has shifted toward more discoveries based on the underlying mechanism of disease, especially in new cancer drug discovery. Through a particularly robust clinical trial and commercialization infrastructure, Penn has further worked to smooth every part of the path from idea to implementation. And to ensure that state-of-the-art treatments reach the patients who need them, Penn Medicine teams have also kept focus on equity and access during clinical trials and after therapies are approved.

In the long view, Penn’s emergence as a hub for medical advancements that lead to drug research and development is a credit to both the culture and strategic choices going back decades, said Jonathan A. Epstein, MD, executive vice dean and chief scientific officer in the Perelman School of Medicine.

“Our leadership has been judicious about investing in a broad portfolio across a pipeline of development that might take 20 or 30 years,” Epstein said. “People here embrace a no-risk, no-reward approach—they aren’t afraid to take the long view and realize you have to back many different ideas to end up with just a few breakthrough therapies.”

Reducing barriers to translational research

Hiring Carl June—whose belief that the immune system could be trained to fight cancer was derided by naysayers—in 1999 is one of the risks Epstein references. At the time, nobody predicted June’s work would change the entire trajectory of cancer care.

June began studying CAR T cell therapy in cancer in the late 1990s, and as signs of success grew, so did the breadth of collaborators at Penn Medicine and Children’s Hospital of Philadelphia (CHOP) who brought the method into clinical trials. It would take nearly two decades to achieve FDA approval of the therapy in 2017 as a treatment for advanced acute lymphoblastic leukemia. The groundbreaking technique involves taking T cells—part of the immune system—from a patient’s blood and engineering them to produce CARs before reinfusing them into the body. These new receptors latch onto unique antigens on the patient’s tumor cells, killing them. Marketed by Novartis as Kymriah, the first CAR T cell therapy has proved lifesaving for many patients whose cancer has relapsed or failed to respond to other therapies. It has since garnered two additional approvals from the FDA to treat other forms of cancer.

Similar stories have played out on campus over and over. Jean Bennett, MD, PhD, and Albert Maguire, MD, were also “risky” hires whose ambitions vexed skeptics when they joined Penn’s Scheie Eye Institute in 1992. But their determination and decades of work from basic science through to clinical trials at Penn and CHOP, paid off; in December 2017, less than four months after approving CAR T, the FDA approved the married team’s treatment for a rare form of congenital blindness called Leber congenital amaurosis. Marketed as Luxturna, the therapy restores patients’ eyesight by injecting a corrective gene directly into their eyes via a viral vector. It was the nation’s first commercialized gene therapy—a term that encompasses a collection of techniques to modify a patient’s DNA—for a genetic disease.

Eighteen months later, approval followed for Zolgensma, a gene therapy using a viral vector developed in the lab of James Wilson, MD, PhD, director of Penn’s Gene Therapy Program and Orphan Disease Center, and studied in trials at CHOP, to correct spinal muscular atrophy — the number one genetic cause of infant mortality.

And in the most ubiquitous novel advance tied to Penn Medicine, in August 2021 the FDA gave its first full approval to an mRNA-based COVID-19 vaccine, which uses technology discovered more than 15 years earlier by longtime research partners Drew Weissman, MD, PhD, the Roberts Family Professor in Vaccine Research, and Katalin Karikó, PhD, an adjunct professor of Neurosurgery.

Recruiting faculty who dream big is essential to drug development, but there are other reasons Penn Medicine has connections to so many cutting-edge therapies. Among the top, said Vonderheide, is a strategic emphasis on translational research and eliminating barriers between laboratories and the clinic.

“Even our building design reflects that value. If you stand in the lobby of the Perelman Center for Advanced Medicine, you're within 100 yards of the labs where discoveries are being made, the clinics where clinicians are designing clinical trials and patients are getting therapies, and the offices where executives are working out financial models,” he said. “We're a unified, integrated system committed to making science real for patients.”

Financial investment from the health system is key to moving discoveries toward the clinic and helping more patients, Epstein added, citing the Perelman School of Medicine’s Clinical Cell and Vaccine Production Facility—where cell and gene biotherapeutics are manufactured to meet regulatory standards—as an example.

“The health system invested in what was only basic research at the time to build the good manufacturing practices facility that is necessary to produce things like CAR T cells safely so they can be put back into humans,” he said. “Facilities like that cost a lot, and most medical schools can’t afford them. But at Penn Medicine we integrate our clinical and research missions intentionally, for the sake of the patients who don’t have the best clinical options today. We can’t afford not to invest back into ongoing scientific discovery.”

Expanding new categories of therapies pioneered at Penn

The FDA approval of a drug doesn’t mean its development ends, particularly in young and still-unfolding categories like cell and gene therapy and mRNA technology. Research around the world has proliferated in these new realms, where Penn Medicine faculty are still striving to push the science forward.

While CAR T cell therapy has revolutionized treatment for hematologic malignancies, researchers are still striving to use it successfully against solid tumors; getting the treatment to penetrate solid masses is one challenge, and it is harder to find unique antigen proteins to target on solid tumor cells. Faculty members are examining ways to overcome these limitations, such as delivering CAR T cells regionally and testing multivalent CARs, which simultaneously bind to multiple targets.

Researchers are also pursuing universal “off-the-shelf” versions of CAR T, which would spare patients from having to donate their own T cells for engineering—saving precious time while ensuring an abundance of high-quality cells to work with. And many are studying CAR T therapy in conditions other than cancer—including Epstein, who is evaluating CAR T cells’ ability to treat fibrosis, which can affect any organ and is a major driver of heart failure.

In terms of gene therapy, most activity to date has tackled rare diseases, but some faculty are on a mission to change that—like cardiologist Kiran Musunuru, MD, PhD, MPH, ML, director of the Genetic and Epigenetic Origins of Disease Program. Musunuru is applying the gene editing technology CRISPR to fight the leading cause of death worldwide: cardiovascular disease. He has found that modifying genes in the liver can permanently reduce a person’s cholesterol levels and protect against heart attack and stroke. Currently in a clinical trial in New Zealand and the U.K., this single shot could eventually work as a heart disease “vaccine.”