麻豆传媒

The approval of a second CAR T-cell therapy within 2 months signals the start of expanded investigation of the therapy in hematologic malignancies and possibly beyond, a principal investigator said.

Approved by the FDA for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), axi-cel (Yescarta) enters a larger disease field as compared with tisagenlecleucel (Kymriah), which received FDA approval for children and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL). DLBCL is the most common form of non-Hodgkin's lymphoma (NHL) and often has an aggressive clinical course.

More than 10,000 patients die of DLBCL each year, and axi-cel could have an almost immediate impact on that mortality, said Frederick Locke, MD, of Moffitt Cancer Center in Tampa, Florida.

"Speaking only for my practice, I intend to use these two products for, number 1, consideration of a clinical trial for any patient who might be eligible, and, number two, if we use these commercially available products as standard of care for relapsed DLBCL and relapsed ALL, it will be the one that is FDA approved for that condition," he told 麻豆传媒. "That's not to say they won't eventually have competing indications."

Currently, the principal candidates for the therapy are patients whose disease progressed through the most recent line of chemotherapy and those whose disease relapsed within 12 months of an autologous stem-cell transplant, he added.

Beyond Approval

Locke led the pivotal ZUMA-1 trial of axi-cel, results of which provided the key data to support the application for FDA approval. The data showed an objective response rate of 82%, which included many patients whose disease had progressed on multiple prior lines of therapy. Overall clinical experience with axi-cel has been remarkable, he said.

Work has already begun on trials to evaluate CAR T-cell therapy in earlier stages of disease and in other types of hematologic malignancies, especially other forms of NHL, which collectively has 72,000 new diagnoses each year. Additionally, interest has emerged in the potential of CAR T-cell therapy for treatment of solid tumors.

Both of the approved therapies target CD19, a protein expressed in the surface of lymphoma and leukemia cells. The primary difference between the two products is the co-stimulatory domain. Upon binding CD19, the drugs induce different co-stimulatory signals to activate an immune response.

"We still don't know enough to say whether one is better than the other," said Locke.

Production time for the personalized therapy initially was a concern, given that many patients who are candidates for the disease are critically ill. Locke said turnaround time for both CAR T-cell therapies has improved.

During ZUMA-1, 17 days passed from the time a patient's T-cells were harvested, shipped to the manufacturer's central processing lab and genetically modified to recognize CD19 protein, and then returned to the treating center. Additionally, usable cells were obtained for all but one of the 111 patients enrolled in ZUMA-1.

Beyond Efficacy

The therapy has well-documented side effects -- notably, cytokine release syndrome and neurologic toxicity. Without minimizing the potential severity of the effects, Locke said investigators in ZUMA-1 found the toxicity manageable.

Neither therapy will be available to all comers, at least initially. Instead , a controlled launch is planned, focusing on centers that have appropriate facilities, standards, and training for CAR T-cell therapy. Centers accredited by the Foundation for Accreditation of Cellular Therapy will meet most of the criteria, and the drug manufacturers will provide additional training specific to CAR T-cell therapy, said Locke. Within a year of the launch, officials at Kite Pharmaceuticals, recently acquired by Gilead Sciences, hope to have the therapy available at .

The therapy comes with an impressive price tag, estimated at per patient. However, some authorities project the total cost -- including hospitalization, other treatment, and management of side effects -- could reach .

Acknowledging cost as an issue that has received a lot of attention, Locke said, "I can't speak to cost. All I can say is that this is a potentially very valuable therapy. This is a therapy that for patients treated in the early-phase studies at the National Cancer Institute ... they are now 4 years out and more, who are in remission after a single infusion of these CAR T-cells. There is a lot of value for this therapy, particularly for patients with no other treatment options; they are out of options."

Experts Weigh In

Other experts in CAR T-cell therapy echoed Locke's sentiments that the two FDA approvals are just the beginning for a therapy that will have a potentially transformative effect on hematology and possibly other areas of oncology.

"While the Food and Drug Administration's first approval of a CAR T-cell therapy impacted a relatively small number of pediatric and young-adult patients, [yesterday's] decision opens the door for a cellular immunotherapy to treat adults with aggressive lymphoma. There will likely be thousands of lives saved in the next few years because of it," David Maloney, MD, medical director of cellular immunotherapy at Fred Hutchinson Cancer Research Center in Seattle, said in a statement. "The FDA's ruling validates the revolution under way in the field of cellular immunotherapy, which enables us to engineer patients' own immune systems to eliminate cancer cells. We at Fred Hutchinson Cancer Research Center believe that by 2025 there will be many approved T-cell therapies for a variety of cancers."

Armin Ghobadi, MD, of Washington University's Siteman Cancer Center in St. Louis, said: "This is the beginning of a new era of cancer therapy. With CAR-T cell therapy, we can take patients' own cells and turn them into a powerful weapon to attack cancer. It's a highly personalized, innovative therapy and one we hope also will prove to be effective against many different types of cancer."

James L. M. Ferrara, MD, DSc, of Mount Sinai Medical Center in New York City, called the FDA action "great news for cancer patients" -- The approval, he said, "proves that gene therapy is here to stay, and is likely to help increasing numbers of patients with terrible blood cancers that don't respond to standard treatments. These are highly personalized therapies, and this success will accelerate efforts to make such treatments available for large numbers of patients."

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