CAR T-Cell Therapy Approved by FDA for Mantle Cell Lymphoma

August 24, 2020, by NCI Staff

Micrograph of mantle cell lymphoma that has invaded the small intestine.
Credit: Michael Bonert (via Wikimedia Commons), CC BY-SA 3.0

On July 24, the Food and Drug Administration (FDA) approved an immunotherapy for some patients with mantle cell lymphoma, a fast-growing cancer of the blood that has proven difficult to treat effectively.

The new treatment, a CAR T-cell therapy called brexucabtagene autoleucel (Tecartus), was approved for patients with mantle cell lymphoma that does not respond to other treatments or has recurred.

Mantle cell lymphoma arises in B cells, a type of white blood cell. Most people with mantle cell lymphoma are diagnosed with an aggressive form of the disease that has already spread.

FDA’s approval was based on a clinical trial, called ZUMA-2, that tested brexucabtagene in 60 patients with mantle cell lymphoma who had received up to five prior treatments.

In the trial, 87% of the patients responded to a single infusion of brexucabtagene, and 62% of the patients had a complete response, meaning that they no longer had signs of the disease, at least temporarily.

All the patients had previously been treated with a drug that blocks the activity of BTK, a protein involved in the growth and survival of some cancers.

“Our study showed that CAR T-cell therapy has the potential to overcome the resistance of mantle cell lymphoma to other available therapies,” said Michael Wang, M.D., of the University of Texas MD Anderson Cancer Center, who led the clinical trial.

Like other CAR T-cell therapies, the drug may cause serious and potentially life-threatening side effects in some patients. These include cytokine release syndrome, which can lead to a high fever and flu-like symptoms, as well as neurologic effects, which can cause a patient to enter a comatose state.

Three of the 60 patients in the trial died as a result of treatment-related side effects, said Dr. Wang. Without the CAR T-cell therapy, Dr. Wang continued, all the patients in the study would have been expected to die of mantle cell lymphoma in less than a year.

“This therapy is a major advance for the treatment of relapsed and treatment-resistant mantle cell lymphoma and should be considered in all patients with the disease,” said Mark Roschewski, M.D., who studies lymphomas at NCI’s Center for Cancer Research and was not involved in the clinical trial.

“The approval will be critical for the care of patients whose cancers are resistant to BTK inhibitors,” Dr. Roschewski continued. “In general, these patients have a poor prognosis, and some develop a very aggressive form of the disease immediately following the use of BTK inhibitors.”

A Customized Cancer Treatment

Brexucabtagene is the first FDA-approved CAR T-cell therapy for mantle cell lymphoma. The other approved CAR-T cell therapies for cancer are tisagenlecleucel (Kymriah) for acute lymphoblastic leukemia and axicabtagene ciloleucel (Yescarta) for diffuse large B-cell lymphoma. All three drugs target a protein on cancer cells known as CD19.

Researchers are also investigating CAR T-cell therapies as possible treatments for many other cancers, although to date the most success with these treatments has involved blood cancers. In addition, NCI has launched an initiative to manufacture CAR T-cell therapies for clinical trials being conducted at multiple hospitals.

Each dose of brexucabtagene is manufactured using a patient’s T cells, a type of white blood cell that attacks viruses and tumors. In the lab, the T cells are genetically modified to recognize and kill the person’s cancer cells; the modified cells are then grown in the laboratory to increase their numbers and given to the patient as a one-time therapy.

Over the past decade, several new drugs, including the BTK inhibitors acalabrutinib (Calquence) and ibrutinib (Imbruvica), have expanded treatment options for mantle cell lymphoma. But more-effective treatments have long been needed, according to Dr. Wang.

“I became interested in CAR T-cell therapy because this disease is not cured by existing therapies, such as chemotherapy and targeted therapies, or even by combinations of these agents,” said Dr. Wang, who led the international clinical trials that resulted in the approvals of acalabrutinib and ibrutinib for patients with mantle cell lymphoma.

Many patients with mantle cell lymphoma experience repeated cycles of remission and relapse until the disease eventually becomes fatal, he explained.

“Mantle cell lymphoma has historically had one of the worst prognoses of any B-cell lymphoma, because the disease can be very aggressive and chemotherapy does not provide a cure,” said Dr. Roschewski. “Virtually all patients are expected to relapse at some point.”

Until now, patients with mantle cell lymphoma have received treatment indefinitely, he continued. “CAR T-cell therapy does not require treatment indefinitely, and it may potentially cure some patients,” he said.

Results from the ZUMA-2 Trial

In the ZUMA-2 trial—which was funded by Kite Pharma, the manufacturer of brexucabtagene—participants received a conditioning regimen that included chemotherapy followed by a single infusion of the CAR T-cell therapy. At a median follow-up of 12.3 months, 57% of the 60 patients in the study were in remission.

Longer follow-up is needed to determine the median amount of time patients treated with the drug survive, noted Dr. Wang.

“We cannot say yet whether some of these patients who experienced complete responses are cured—as that will take much longer follow-up,” said Dr. Roschewski. “It is possible that some are cured, or it is possible that this will only delay the timing of relapse.”

More research is also needed to better understand which patients are more likely to respond to CAR T-cell therapy versus other agents, such as combinations of targeted drugs, Dr. Roschewski noted.

He added: “These are important additional questions that will likely be addressed with future studies.”

The most common side effects included lower-than-normal levels of certain white blood cells, infections, and a weakened immune system. One patient in the trial died of cytokine release syndrome, and two patients died of complications from infections, according to Dr. Wang.

“The treatment can make people prone to infections, which are a major concern,” said Dr. Wang. “CAR T-cell therapy has never been a very easy therapy for patients to receive.”

Kite’s commercial manufacturing facility in El Segundo, California, will manufacture brexucabtagene for all patients, according to a statement from the company. In the ZUMA-2 trial, it took a median of 15 days from leukapheresis—a laboratory procedure in which white blood cells are separated from a blood sample—to the delivery of the therapy.

A relatively short turnaround time is critical for treating advanced mantle cell lymphoma, because patients are very ill and the disease may progress rapidly, the manufacturer noted.

Dr. Wang was a research fellow at the Fogarty International Center at NIH and trained with NCI investigators early in his career. “That work—studying cell biology and molecular biology in the laboratory—paved the way for the research on mantle cell lymphoma I am doing now,” he said.