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November 18, 2016
CAR T-Cell Therapy Moves Closer to FDA Approval

Dr. Carl June speaks at WALS lecture.
Dr. Carl June speaks at WALS lecture.

Currently, there are few options for patients with relapsed and treatment-resistant blood cancers. A new approach to immunotherapy might give those patients another avenue, said Dr. Carl June at a recent NIH Director’s Lecture in Masur Auditorium.

The approach, called chimeric antigen receptor (CAR) T-cell therapy, is expected to be approved next year by the Food and Drug Administration for the treatment of blood cancers such as leukemia and lymphomas, said June, a professor of immunotherapy at the Perelman School of Medicine at the University of Pennsylvania.

The CAR T cells nearing approval are genetically engineered to seek out and destroy leukemia cells. There are several types of leukemia, including chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL).

To prepare CARs for therapy, white blood cells called T cells are taken from a patient. Then they are “genetically modified in the lab and returned to patients, usually after some sort of conditioning, like chemotherapy,” he said. “CARs are synthetic molecules. They don’t exist naturally.”

The gene for a receptor that binds to the CD19 antigen is added to T cells. CD19 is a protein found on the surface of all B cells, a type of white blood cell. June called CD19 a “dream target” because it’s expressed on the surface of every B-cell malignancy, including CLL and ALL. Although healthy B cells are killed during therapy as well, they can be replaced.

Serious side effects of the treatment include cytokine release syndrome (the so-called “cytokine storm”) and tumor lysis syndrome. Symptoms of cytokine release syndrome are high fever and drop in blood pressure. Tumor lysis syndrome is a complication of treating a fast-growing cancer. When cancer cells are destroyed, they break apart and release their contents into the bloodstream. Left untreated, it can cause kidney failure and irregular heart rhythms. For both syndromes, the severity depends on the cancer’s size.

June first began genetically modifying T cells in the mid-1990s, when he was studying HIV/AIDS. Then, he and his colleague Dr. Bruce Levine thought they might be able to modify T cells to kill HIV, the virus that causes AIDS. He gave patients infusions of CAR T cells every 30 to 60 days. Although the modified cells didn’t have an antiviral effect, they proved safe.

“We found in 2012 that, in fact, 36 out of 39 patients we treated still had CARs—out past a decade,” he noted. “We think they persist longer than natural T cells.”

He and colleague Dr. David Porter first treated 14 patients with incurable CLL in 2010. That study had an overall response rate of 57 percent. Four patients had a complete response and four more had a partial response. Six patients had no response. Of the patients who had complete responses, “we’ve had no relapses. It’s effective in a subset of patients,” June noted.

June first began genetically modifying T cells in the mid-1990s, when he was studying HIV/AIDS.
June first began genetically modifying T cells in the mid-1990s, when he was studying HIV/AIDS.


In some patients who did relapse, the CAR T cells didn’t proliferate “for reasons we don’t understand,” he said. In other cases, the cells could not find their target because the tumor mutated. If CD19 is no longer on the surface of a B cell, the CAR T cell can no longer find the cancer.

Clinical trials are under way at Penn and other institutions to develop and test CARs that seek and destroy multiple targets.

Between 2012 and 2016, June and his team treated 60 pediatric and young adult patients with ALL; 93 percent had a complete response.

“The results we’ve seen in ALL have been more dramatic than CLL,” he said.

As of May 2016, June enrolled 368 patients in CAR T-cell clinical trials. Not one had a “genotoxic event,” where damage to cells can lead to mutations or deletions that can later cause cancer.

June expects the FDA will approve CARs for CD19-specific malignancies such as leukemia and lymphoma in 2017. Even though this therapy is nearing approval, there are significant challenges that must be addressed, he cautioned.

At first, CAR T-cell therapy will only be available at high-end “quaternary” cancer centers. Physicians practicing at community hospitals won’t be sufficiently trained in immunotherapy, so they can’t offer it to patients. How T cells are produced will also limit the availability of treatments.

“We need robotic and fully automatic cell culture,” said June. “We have a system that still depends on academic-based manufacturing systems—basically requiring highly trained personnel.”

Since CAR T-cell therapy is personalized, new T cells must be grown from a patient’s own cells. June said it isn’t clear yet whether cord blood or T cells from a healthy donor can be used.

Unfortunately, he has not had the same success in patients with solid tumors because “most tumors have targets on the surface essential for other normal cells.” Complex sugars found only on the surface of tumors, however, might be alternative targets for therapy.

Currently, June’s lab is conducting clinical trials in patients with multiple myeloma, a cancer of plasma cells, and in patients with pancreatic cancer to test whether certain glycans can serve as effective targets.

June concluded by noting that when he first started treating leukemia patients in 2010, there were only three cancer centers with open CAR T-cell trials. Now, there are 110 trials open in the U.S and around the world, evidence for the global emergence of a new therapy.

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