June's Quest to Develop Gene Therapies Is a Neverending Research Story

Published: Wednesday, Nov 30, 2016
Carl H. June, MD

Carl H. June, MD

As with software upgrades, Carl H. June, MD, sees his work in cancer research as a job with ever-evolving updates.

June was honored with a 2015 OncLive Giants of Cancer Care Award® for his work with chimeric antigen receptor (CAR) therapy in patients with different subtypes of leukemia and lymphoma. Such research, which uses the patient’s own white blood cells to help destroy tumors, is “an ultimate form of personalized medicine,” said June, speaking with OncLive in a video interview.

“It’s kind of like computer systems, where we’re just seeing the launch of Windows 10,” he said. “What we have right now is CAR 1.0, and [the research will] get better and better with next generations. I’m very excited about that prospect—it will be both more potent and safer with what’s going to come.”

CAR therapy has been studied in adults with chronic lymphocytic leukemia (CLL) and adults and children with relapsed/refractory acute lymphoblastic leukemia (ALL). It was heralded with a breakthrough therapy designation from the FDA for ALL in 2014 for the investigational therapy CTL019.

June’s success in testing CTL019 has helped launch robust development in the field. These days, about a dozen teams of academic researchers are currently evaluating various CAR agents in CLL and ALL, according to the Cancer Research Institute. CTL019 is being developed through an agreement between the University of Pennsylvania, where June is the Richard W. Vague Professor in Immunotherapy at the Perelman School of Medicine, and the pharmaceutical company Novartis. The company is expected to file a new drug application for CTL019 in 2017.

June also is moving forward on the adoptive cellular therapy front with other projects. He is among the prominent researchers working with the Parker Institute for Cancer Immunotherapy, a collaborative funded by technology entrepreneur Sean Parker. He is serving as scientific adviser on the institute’s efforts to use emerging CRISPR gene-editing technology to create a novel immunotherapy for a first-in-human clinical trial.

How CTL019 Works

The field of adoptive anticancer immunotherapy has had many disappointments over the years, but the tide began to turn when researchers started developing CAR T-cell agents that could kill tumor cells that employed escape mechanisms, June noted in a 2015 video interview with the journal Immunological Reviews. He said the ability to develop antibodies with a higher affinity for receptors than T cells also has enabled the therapies to advance.

CTL019 is manufactured from the patient’s white blood cells, which are engineered over a 5-to-10-day process to become leukemia-specific killers that are then reinfused into the patient, June explained. He calls the cells “serial-killer T cells.”

“We found that each of these gene-modified CAR cells that we transfused into the patient can be responsible for killing more than a 1000 tumor cells,” he said. “There’s no precedent for that—where the cells are both a living drug and they divide in the body, so the body becomes, actually, a bioreactor.”

The technique differs from other cancer treatments because of gene modification. “It’s gene transfer technology that makes the cells chimeric, so they have the properties of other cells, but they are not found naturally in the body,” said June. It’s a case of synthetic biology, of making the immune system better than it was before the transfusion.

Another remarkable element is how treated CAR T cells in the body are on patrol to attack cancer cells. “These cells are living drugs. We still detect CAR T cells in patients infused 5 years ago. They’re hunter cells, and that’s the power of the immune system. It can have a memory—in this case of the cancer cells—and it can prevent the tumor from coming back,” June said.

A noteworthy milestone with CAR technology occurred in July 2015 when the first patient treated with CAR T cells celebrated a half-decade of remission. “He just passed the 5-year mark and remains free of leukemia, which was his initial form of cancer,” June said. “He’s enjoying his retirement.”

An Improvement Over Transplantation

CAR T-cell therapy is also notable for how it prolongs life, particularly when compared with bone marrow transplants—the traditional treatment for these types of cancer, June said. “When I began training on bone marrow transplantation in the early 1980s, we had what was called the rule of 10. For each decade of life, you had a 10% chance of dying. So if you were 30, you had a 30% chance of dying after a bone marrow transplantation.

“With time, bone marrow transplantation has gotten much safer and the same thing will happen with CAR T cells,” he said.

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