Penn Medicine’s flash mob celebration of the first CAR T cell therapy approval
The first-of-its-kind FDA approval of an immune cell therapy for cancer was big news on Penn’s campus. It marked the culmination of a chapter of discovery, collaboration, and spectacular feats of surviving once-deadly cancers. And it’s the start of much more.
On the morning of August 30, 2017, the U.S. Food and Drug Administration announced what was called an “historic action”: A University of Pennsylvania-developed personalized cellular therapy was approved for the treatment of advanced acute lymphoblastic leukemia (ALL) in children and young adults. Hours later, the newly minted director of the Abramson Cancer Center (ACC), Robert Vonderheide, MD, DPhil, found himself atop a coffee stand in the lobby of the Perelman Center for Advanced Medicine, looking out over a crowd that numbered in the thousands who had gathered to celebrate, all beaming with pride and joy.
Carl June, MD, the pioneer who led Penn’s charge into this new cancer frontier, had just arrived.
“This is absolutely an amazing day,” Vonderheide said. “There’s just one thing I want to tell you…‘the Abramson Cancer Center is on fire.’”
Before that bright crowd, Vonderheide didn’t have to explain much.
They knew that it was the first time the FDA had approved a therapy based on gene-transfer technology that used a viral vector to insert genetic material into a T cell. It was the first time the agency had approved a personalized therapy that used a modified version of a patient’s own cells as a treatment. And it was a major moment in the unfolding renaissance of exciting developments of therapies that empower the body’s immune system to fight cancer. They had seen the lives saved in their own hospital during the early, experimental days of using the treatment, and they knew what its approval signified, for more lives in more places.
The radical idea
Even 10 years earlier, the moment would have been considered a pipe dream.
The immunotherapy field was still relatively small, with few research groups around the world investigating ways to manipulate the immune system’s T cells to fight disease. Pharmaceutical companies had little interest. Funding was scarce. And people from other biomedical fields largely viewed as a low priority.
None of this seemed to discourage June, an immunologist who had been working with modified T cells to develop experimental HIV therapies since the mid-1980s. By the time he and his then-postdoctoral researcher Bruce Levine, PhD, now the Barbara and Edward Netter Professor of Cancer Gene Therapy in the department of Pathology and Laboratory Medicine, landed at Penn in 1999, they had cracked the code on how to get T cells to grow outside the body, and safely infused a small group of HIV patients with first-generation chimeric antigen receptor (CAR) T cells that enhanced their immune function. Blood cancers would be next.
“People advised me to think carefully about working with Carl because they said the work he was doing was high-risk and unlikely to be successful,” said Michael Milone, MD, PhD, an associate professor of Pathology and Laboratory Medicine, who joined June’s lab in 2003 as a postdoc and helped develop a CAR T cell designed to find the CD19 protein expressed on B cells. “Happy to prove them wrong!”
Training the body’s immune system to fight cancer
Penn Medicine is where the world's first CAR T cell therapy was invented, and it holds promise for a cure for many cancers.
‘Spectacular’ results
By 2009, the team, which by then included David Porter, MD, director of Blood and Marrow Transplantation in the ACC, was ready for human testing of that CAR T cell, which became known as CART19 and later, as CTL019. The National Institutes of Health had declined to fund the work several times over the years, but help from private funders allowed the researchers to now conduct a small trial—just three patients. Out of options to treat aggressive chronic lymphocytic leukemia (CLL), these three Penn patient-pioneers said yes to trying one more thing.
A billion or so of their T cells were removed, reprogrammed with a modified, harmless HIV virus and taught to seek out that CD19 protein on cancer cells, and then infused back into their bodies to multiply and attack.
A year later, results from that trial—two of the three patients experienced complete remissions of their disease, and a third had a partial response—published in the New England Journal of Medicine and Science Translational Medicine grabbed people’s attention. Headlines the next day read, “‘Huge’ Results Raise Hope for Cancer Breakthrough” and “Immune System, Loaded with Remade T-cells, Vanquishes Cancer.” Calls and emails from more than 5,000 patients and desperate family members poured in to the research team, asking if the therapy was ready to help them, too. And the news caught the pharmaceutical industry’s eye.
By 2012, June and his team, in close partnership with the Penn Center for Technology Transfer (now the Penn Center for Innovation), formed an alliance with global giant Novartis to accelerate research, development, and commercialization of CAR therapies. Trials in adults and pediatric patients from Children's Hospital of Philadelphia (CHOP) with another blood cancer known as acute lymphoblastic leukemia (ALL) also got underway, with Stephan Grupp, MD, PhD, director of the Cancer Immunotherapy Frontier Program at CHOP and the Novotny Professor of Pediatrics at Penn, taking the clinical trial helm at CHOP. Noelle Frey, MD, an assistant professor of Hematology-Oncology at Penn, joined Porter to lead the adult trials.
“These patients in general had a life expectancy of three months, and 90 percent of them had complete remission,” June said. “It was just spectacular.”
Success of the pediatric trial led to a global trial for advanced ALL that began in 2015 at 25 centers around the world. The results were equally spectacular: Of 68 children and young adults, 52 patients achieved complete remission.
Verge of approval
Six months after researchers published those results, in July 2017, Tom Whitehead, the father of Emily Whitehead, Grupp’s patient at CHOP and the first pediatric patient to receive CTL019, stood before an FDA panel in Washington, D.C., imploring them to recommend the drug’s approval. Emily, who was near death on her seventh birthday, has since been cancer free for over five years. “We believe that when this treatment is approved, it will save thousands of children’s lives around the world,” he told them.
The committee reviewed the data and said yes, in a unanimous vote. Forty-nine days later, the therapy, marketed by Novartis as Kymriah, officially became approved. Soon after the August 2017 approval, patients with ALL up to age 25 who had exhausted all other options could receive it at roughly 30 centers across the country, including Penn and CHOP. That’s about 600 patients per year, to start. In the aftermath of the approval, questions about costs of the therapy remained a part of the public discussion. But on August 30, 2017 the focus was on celebration of this historic moment.
Cell-ebration
Back at Penn’s Perelman Center, June was now walking through the crowd like an esteemed conductor heading to his orchestra. Vonderheide stepped down from the coffee stand, and June took his place. He kept it short, too.
“Today, the cancer world has changed forever,” he said. “And I will never forget it.”
Cheers erupted from the crowd.