CART-19: A Leukemia Breakthrough
A Main Line Doctor leads the Penn Medicine research team.
Dr. Carl June’s children call him the “Mouse Doctor.” “People would ask them what kind of doctor I am,” says June, who lives in Merion. “They’d answer that I work with mice, and that that’s what the MD stands for.”
His kids now know the full story—and so will the rest of the world. June’s research has led to the first effective treatment for several forms of adult and pediatric leukemia. With teams at Penn Medicine and the Children’s Hospital of Philadelphia, June has created genetically reengineered immune cells that target the CD19 antigen. Treatment with chimeric antigen receptor-modified T cells—or CART-19 for short—has led to sustained remissions for many patients with the nastiest forms of the disease: acute lymphoblastic leukemia and chronic lymphocytic leukemia. The results of June’s Phase II clinical trials were announced in late 2013 and confirmed by other medical centers. “It’s not a cure,” June cautions. “But this is the most hope we’ve had for finding one.”
CART-19 doesn’t require surgery or hospitalization. The several-step process begins with leukapheresis, which extracts immune cells (T cells) from the body. “The patient sits in a chair with IVs in each arm,” says Dr. David Porter, part of the CHOP team and Abramson Cancer Center’s director of blood and marrow transplantation. “Through one, blood is pumped out of the body and sent into a machine to separate T cells from other cells. The blood returns to the body through an IV in the other arm.”
Uncomfortable but not painful, it takes about four hours. Only 1 percent of the body’s T cells are removed, so the immune system is not compromised.
After leukapheresis, the patient heads home, and the T cells go to June’s lab. There, they are purposefully infected with a virus that triggers a response in them. They grow stronger and multiply, bulking up into an army of T cells. The process takes two weeks, during which the patient undergoes several rounds of chemotherapy to rid the body of its exhausted T cells. The mega-strong T cells are then infused into the patient, and they go “hunting” for leukemia cells. “Think of a leukemia cell as having Velcro on it,” Porter says. “The new T cells have another piece of Velcro. Once they stick, they become highly activated killers, eliminating the leukemia cells.”
And the T-cells get stronger with each battle. Unlike other reengineered cells, these keep growing after they’re inside the body, often multiplying as many as 10,000 times. “They’re like a living drug,” says Porter.
There is, however, a potentially dangerous side effect: Cytokine release syndrome is the body’s inflammatory response to those juiced-up T cells. It results in high fevers, muscle and joint pain, dangerously low blood pressure, and breathing problems. Immunomodulators are effective in blocking interleukin-6’s damage, but the Penn Medicine team is looking for other solutions.
June’s CART-19 discovery fuses two halves of his career: leukemia and HIV research. “At a 40,000-foot view, the issue with both diseases is that they disable or kill T cells,” says June. “I thought, ‘What if we use part of one disease to kill the other?’ It’s how we started using an inactive form of the HIV virus in the leukemia research. Now we can grow T cells to replenish the body’s immune system.”
FDA approval for CART-19 will come upon completion of Phase III clinical trials. In the meantime, June and his team will focus on two goals: duplicating the treatment to make it available at medical centers around the world, and researching how to make CART-19 work for other kinds of cancers.
And that’s where Novartis comes in. The pharmaceutical giant has licensed CART-19 from Penn Medicine. In exchange, the company is building a state-of-the-art lab at Penn called the Center for Advanced Cell Therapies. “I’m looking out my window at the cranes,” June says. “That’s where the next phase of my career will begin.”