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

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.

How CTL019 Works

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.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.

An Improvement Over Transplantation

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.”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.

Relatively few patients who have been treated with CAR T-cell therapy in clinical studies have died from adverse effects. Also, CAR T-cell therapy can help patients at earlier stages of cancer development, which is when they have virtually no risk of cytokine-release syndrome, an infection-like response that can cause high fevers, low blood pressure, and pulmonary edema. Being able to administer therapy earlier to patients also allows for more treatments to take place in settings other than specialized oncology units.

“In very late-stage leukemias, about one-third of the patients need to be cared for in intensive care environments found in cancer centers, but we found that as you move to do this earlier on in patients—where they don’t have such advanced disease and high levels of cancer—that it could be done in a community-hospital setting as an outpatient therapy,” June said.

Ultimately, such treatment could change the course of cancer treatment. “Right now, when patients get leukemia, the first line of therapy is chemotherapy and/or radiation therapy,” he said. “What we would like to use is a targeted immune therapy and replace the need for chemotherapy.”

CAR T-cell therapy is also being examined for use in treating other types of cancers, with ongoing trials studying patients with lymphoma and myeloma. “And then the big question in the field is solid cancers and what the role of this kind of immunotherapy will be,” June said.

June believes that sharing knowledge and educating others about scientific advances in the field of immuno-oncology is crucial. “It’s important for scientists to talk, so that the public can learn about these new kinds of therapies,” he said. “Most physicians have very little understanding about how the immune system really works, especially in the field of oncology where, until just recently, there was no immunotherapy.

Path to Discovery

“Education is really important so there’s not a barrier to this going forward and [it is] being used in a way that patients receive the most benefit,” he said.Although June had an early interest in cancer research, his path to immunotherapy experimentation was rather circuitous, he recalled in the Immunological Reviews interview. He had been accepted to Stanford University in 1971 when the Vietnam War intervened. June was drafted to serve in the military so he ended up attending the US Naval Academy at Annapolis, graduating in 1975 with a bachelor’s degree in biology.

He subsequently obtained his medical degree at Baylor College of Medicine and went on to postdoctoral training in transplantation biology at Fred Hutchinson Cancer Research Center in Seattle. In the early 1990s, June joined the Naval Medical Research Institute, where he founded the Immune Cell Biology Program and served as head of the Department of Immunology.

Because of funding restrictions, however, June was not able to pursue anticancer immunotherapies. Instead, his laboratory focused on infectious diseases. “That turned out to be really important when I did move to the University of Pennsylvania in 1999 because we were the first then to begin to use HIV viruses as a tool to reshape cells so that they could be used for adoptive cellular therapy,” June recalled.

Over the years, June has garnered many awards for his work in immunology. Yet the physician—scientist talked about his accomplishments in a humble vein several years ago during a video interview with the Alliance for Cancer Gene Therapy, which has helped fund his work.

“The ability to do medical research is a tremendous honor,” said June. “If it works, it can benefit people. I’ve had loved ones pass away from cancer as other people have and I’ve watched other patients. That motivation makes one get up in the morning to look at yourself in the mirror and say, what have you done to solve the problems?”

Finding success in the field has been “tremendously rewarding,” he said. “I can’t think of a more exciting job.”