Sometimes Tumors Vanish, but Improvements Still Needed for CAR T-Cell Immunotherapy

The Next Frontier

Jonathan Friedberg, M.D., M.M.Sc., director of Wilmot and a worldwide lymphoma expert, is the reason why the cancer center was chosen back in 2016 as one of the first in the nation to evaluate CAR T-cell therapy in diffuse large B-cell lymphoma. Wilmot is still “pushing frontiers,” he says, and will continue to lead as scientists learn more about the treatment.

Reagan and Kim also see promise in combining CAR T cells with other cancer treatments. And manufacturers are speeding up the 10-to-17 days it takes to genetically modify a patient’s immune cells. Data suggest that even modest upgrades in the timeframe could impact survival.

Another major push is around safety, Reagan says. By design, CAR T-cells stir up a powerful immune response, resulting in dangerous inflammation. Patients experience fever and flu-like symptoms, rapid heart rate, low blood pressure, heart problems
and trouble breathing. About 30 percent of individuals also develop short-lived but frightening neurological toxicities: headaches, forgetfulness, confusion, seizures, and coma.

“Somebody who’s really confused or lethargic and possibly on a ventilator presents a lot of other risks beyond the cancer or the treatment,” Reagan says. “Most people who experience serious side effects get better in about a week but it’s very hard on the family. We talk about this leading up to the treatment but it’s still fairly shocking to see.”

Wilmot has been working with several U.S. biotech companies such as Kite, Novartis and Juno Therapeutics, to develop CARs with fewer side effects. The goal is to make the treatment suitable for patients who have disqualifying, underlying health conditions.

Reagan understands the changing landscape as well as anyone. He is part of the U.S. CAR T-Cell Consortium, a group of 17 leading cancer centers that share and analyze the latest data, and conduct innovative clinical studies. As part of the consortium, Reagan was the senior co-author of a high-impact study published earlier this year in the New England Journal of Medicine — the clinical trial with the astounding 93-percent response rate. In that small group (74 patients) with relapsed mantle cell lymphoma, an aggressive disease, 83 percent survived and did well for a year after the treatment. This compares to a 10-to-20 percent success rate for chemotherapy in patients in the same situation.

Wilmot is expanding its CAR T-cell toolbox. It now offers a CAR T-cell clinical trial for children and young adults up to age 21 with acute lymphocytic leukemia (ALL), led by Kristen O’Dwyer, M.D.; and Reagan is planning studies for chronic lymphocytic leukemia (CLL) and other slower-growing lymphomas.

A longer-term goal is to retool CAR T-cells to target solid tumors such as breast, brain and lung. So far, it’s been more difficult for the super-charged immune cells to infiltrate solid tumors, which have more diverse and variable gene mutations. But Friedberg remains confident that investigators will figure out how to overcome the problem.

“In the future,” Friedberg says, “as new CAR T-cell products come into the marketplace, they will be less toxic and will include treatments for earlier stages of blood cancers and other types of tumors. And we’re poised to be ready to take advantage and lead the nation.”

Editor’s note: Photos included in this story were taken prior to the COVID-19 pandemic. Editor

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