Patrick Reagan, M.D., looks at the data on his computer screen and a rare grin spreads across his face. His most recent study results for patients with end-stage mantle cell lymphoma show that an eye-popping 93 percent responded to the latest iteration of CAR T-cell treatment.
He’s not the only one smiling. Oncologists at the Wilmot Cancer Institute and across the U.S., and their grateful patients, are seeing the benefits of one of the most exciting new cancer treatments to emerge in recent years. CAR T-cell therapy is based on an old idea — that the immune system can be super-charged to attack tumors — and thanks to modern technology and a series of new discoveries, it’s showing more promise than ever.
“It’s a miracle in a lot of ways,” says Nicole Zaleski-Conine, 47, an Irondequoit mother of five who underwent CAR T-cell therapy in 2018. “But it’s also science, and doctors, and research and amazing medicine.”
Zaleski-Conine was near death when she received the treatment but remains cancer-free two years later, under Reagan’s care.
CAR T-cell therapy was originally designed for blood cancers. The earliest versions were used to treat pediatric leukemia. Now, adults like Zaleski-Conine, who have a relentless form of diffuse large B-cell lymphoma, may qualify for CAR T-cell therapy when their disease progresses despite standard aggressive treatment.
More recently, as with Reagan’s mantle cell lymphoma study, researchers have been expanding the playbook to other types of blood cancer with success.
“We certainly don’t have other treatments that are as effective in patients who have already exhausted most other options,” Reagan says.
Nationally, approximately 80 percent of patients improve immediately after receiving CAR T-cell therapy, says Reagan, who leads Wilmot’s program to administer the treatment.
Nearly 50 percent of those patients have a complete response, which means their tumors vanish within three months.
Approximately 40 percent stay well for two years or longer, Reagan says, citing national data. These individuals likely would have succumbed to their cancer within weeks or months had they not received CAR T-cell therapy. Instead, they are not only alive, but they’re healthy and productive.
Zaleski-Conine is the 13th of more than 60 individuals who have received the treatment at Wilmot. The positive response rates locally mirror the national data, Reagan says. But as he looks beyond the triumphs to what is still needed, Reagan’s grin fades.
“We have a lot to learn to make the treatment safer and more effective,” he says. “Keep in mind that, ultimately, 60% of patients who get CARs are not going to respond the way we’d like them to with durable remissions, and there are still many people who are ineligible because of other medical problems.”
The barriers to treatment can be heartbreaking: Some individuals with blood cancers and a life expectancy of six months or less either aren’t eligible for the therapy or they don’t live long enough to receive the treatment because their fast-moving disease outpaces the approximately two weeks it takes to fully develop the cells and administer CAR T-cell therapy. In some cases, a person’s weakened body can’t withstand the severe immune reaction, known as a cytokine storm, that occurs, leading occasionally to fatal complications.
“We have a long way to go,” Reagan says.
Science and Safety
One of the most dangerous features of a “living drug” like CAR T-cell therapy is that it cannot be withdrawn from the patient once it’s infused into the veins, says URMC immunotherapy expert Minsoo Kim, Ph.D. In contrast, if a person develops a serious side effect from other types of cancer treatment, such as chemotherapy, the treatment can be stopped.
For this reason, Kim maintains that it’s critical to control the activity of the billions of laboratory-modified immune cells after they’re injected into a cancer-burdened body.
The treatment works like this: A patient’s white blood cells (T cells), which fight off infection and other invaders, are collected and sent to a manufacturing facility to be genetically reprogrammed and expanded. The U.S. Food and Drug Administration has approved a handful of biotech and pharmaceutical companies to produce CAR T-cell therapy, which is designed to attach to the CD19 protein that sits on the surface of some blood cancer cells. After the manufacturing process, the T cells are shipped back to the cancer center and infused into the patient intravenously, where they begin to hunt down cancer.
In 2018, the FDA approved the treatment for adults with certain types of non-Hodgkin lymphoma, and in 2019 it approved a second CAR T-cell drug for diffuse large B-cell lymphoma. The treatment comes with strict eligibility criteria for patients and requires heightened training for the medical team.
Last year, the National Cancer Institute awarded Kim $2 million to investigate the roots of CAR T-cell side effects and to improve its delivery toward tumors. His co-principal investigators are Reagan and Richard Waugh, Ph.D., a University of Rochester biomedical engineering expert.
Kim is most interested in the way CAR T cells act immediately after they get into the bloodstream. Rather than heading straight for cancer, the modified T cells lodge in the lungs, liver, and other major organs for a few days. While there, Kim says, the CARs erroneously recognize non-cancer cells as the enemy and attack healthy tissue. This complicates the body’s immune response.
“Can we inject fewer CAR T-cells to minimize the side effects?” Kim wonders. “If we can figure out how the CARs initially respond, we believe we can ‘direct’ them better toward the intended target.”
“It’s an exciting time,” Kim says, “and we have a great team here at Wilmot.”
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