When immunotherapy professor Carl June started working with CAR T cells, he was not focused on treating cancer.
At the Fred Hutchinson Cancer Center, June studied bone marrow transplantations for patients with radiation exposure during the Cold War, thinking about how to expand T cells — cells that attack foreign invaders in the body as part of an immune response — outside of the body. Later, during the AIDS epidemic, he began using those cells to treat HIV-1 in his lab at the Naval Medical Research Institute.
June’s idea was that a patient’s T cells could be removed from their body, grown in the lab using certain proteins, and returned to the body to continue fighting against HIV-1. Bruce Levine — who now serves as the Barbara and Edward Netter Professor in Cancer Gene Therapy — later joined June in his lab.
But when the pair came to Penn in 1999, they pivoted to looking at CAR T-cell applications in cancer research — specifically, leukemia.
“The Department of Defense does infectious disease work, but they don’t do cancer research,” Levine explained. “We move up to Penn — now we can start clinical trials in cancer.”
“We used the lessons from HIV, but just changed the CAR design and then changed its targeting so that it would target leukemia-associated molecules,” June added. He now serves as the director of Penn Medicine’s Center for Cellular Immunotherapies.
In 2010, the two treated their first patient suffering from chronic lymphocytic leukemia with CAR T-cell therapy. Two subsequent patients in the clinical trial also showed promising results.
“We had treated three patients,” June said. “All three responded, but we had no more money.”
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The field of cancer immunotherapy had, for over a decade, been in what Levine described as “the dark ages of gene therapy,” where skepticism ran rampant, and funding was hard to acquire. The team, with dwindling funds, went ahead and published the results in the New England Journal of Medicine in 2011.
“It’s very unusual in an end-stage cancer trial to have three out of three patients respond,” June added. “We had smoking-gun good evidence that the CAR T cells did it.”
Their work, including the subsequent treatment of pediatric patients, paved the way for the United States Food and Drug Administration’s approval of the first CAR T-cell therapy in 2017.
Now, researchers at Penn are looking at strengthening the effect of CAR T cells — known as “armored” CAR T cells — in blood cancers.
Last year, June helped publish a study that found promising results in using a next-generation “armored” CAR T-cell therapy in patients who continued to resist multiple rounds of other cancer treatments, including commercially available CAR T-cell therapies.
“CAR T-cell therapy has transformed lymphoma treatment, but about half of patients still won’t have a long-term remission,” professor of Medicine at the Hospital of the University of Pennsylvania Jakub Svoboda — who pioneered the 2025 study alongside June — wrote.
“These armored CAR T cells are designed to produce IL-18, which may help them work better in the tumor environment and improve their ability to kill cancer cells,” he explained. “In our first-in-human study, we saw response rates above 80% in patients whose disease had already progressed after standard CAR T-cell therapy, which was very encouraging.”
The 21 patients in the first phase of the clinical trial in the 2025 study had received a median of seven other therapies before enrolling, and all but one had already tried a traditional CAR T-cell therapy approved for their cancer type.
To combat these challenges, a team led by June developed the “armored” CAR T-cell product. This version was modified to secrete a small protein that is capable of enhancing the immune system — which further protects the CAR T cells and promotes their ability to attack cancerous cells.
The research team found strong evidence indicating that adding the protein — interleukin-18 — to CAR T cells contributed to the robust response rates.
But leukemia, a blood cancer, is in the minority when it comes to types of cancer: it is a liquid tumor as opposed to a solid one. With solid tumors, a host of challenges arise.
Now, Penn researchers are devising ways to use CAR T cells to break through barriers — maybe even lowering costs and making the treatment easier on patients’ bodies.
“It’s an incredibly exciting time in the field,” Svoboda wrote when asked to consider the future of CAR T-cell research. “We’re studying newer generations of armored CAR T cells and developing therapies against new targets. What’s especially exciting are approaches like in vivo CAR T cells and allogeneic CAR T cells, which could make these treatments faster, simpler, and more accessible for patients.”
This story is the first part in a two-part series about CAR T-cell research at Penn.
