Treating MCL with CAR T Cells

Chimeric antigen receptor (CAR) T cells targeting CD19 have shown effectiveness in blood cancers, with tisagenlecleucel (Kymriah; Novartis) and axicabtagene ciloleucel (Yescarta; Gilead) approved for acute lymphoblastic leukemia and aggressive large B-cell lymphomas. Based on now-published phase II trial data, a third CAR T-cell therapy could soon be greenlighted for a much rarer hematologic malignancy, mantle cell lymphoma (MCL).

Findings from the ZUMA-2 study of this experimental agent, KTE-X19 (Gilead), were first presented by Michael Wang, MD, of The University of Texas MD Anderson Cancer Center in Houston, during the American Society of Hematology 2019 Annual Meeting. The therapeutic arsenal for MCL is sizeable—from chemotherapy and immunomodulatory drugs to three therapies targeting Bruton tyrosine kinase (BTK)—but “BTK inhibitors are not curative,” Wang notes. Sooner or later, “the majority will become resistant, and at that point, survival is about 6 to 10 months.”

KTE-X19 is similar to its predecessor axicabtagene ciloleucel, with a tweaked manufacturing process whereby circulating tumor cells are removed from the starting material, to better prevent harvested T cells from being prematurely activated and exhausted. ZUMA-2 enrolled 74 patients with relapsed/refractory MCL; all had received up to five prior therapies, including a BTK inhibitor. In a primary efficacy analysis of the first 60 patients, the objective response rate was 93%, with 67% responding completely. At a median follow-up of 12.3 months, more than half of these patients were still in remission. The median duration of response, progression-free survival, and overall survival have not been reached. Side effects, chiefly cytokine release syndrome and neurologic issues, were similar to other axicabtagene ciloleucel trials—and manageable.

Based on these results, KTE-X19 is now under priority review, with the FDA's decision expected by August 10. If approved, “this is the group of patients for whom KTE-X19 would represent a new standard of care,” says Elise Chong, MD, of the University of Pennsylvania in Philadelphia. “We do need long-term remission data, but it's currently one of the most promising agents” for those who relapse after chemoimmunotherapy and whose disease is also unresponsive to BTK inhibition—the majority in ZUMA-2, Chong notes. Given their poor prognosis, “it's encouraging that they still responded to KTE-X19,” she says.

“It's the first time we've seen such good, durable responses even in high-risk patients with, for instance, bulky tumors or the blastoid variant of MCL,” Wang adds. Until now, an allogeneic stem-cell transplant (allo-SCT) would be the only option left to treat aggressive disease. However, the toxicities are severe and successful donor matches are few and far between, he points out.

“The hope is that CAR T would be available to more patients than allo-SCT, with fewer procedure-related complications,” Chong agrees, “but longer follow-up is necessary to know whether it will eventually replace transplantation.”

Wang is also keen to deploy KTE-X19 up front rather than after relapse occurs, at least for high-risk MCL, and plans to spearhead clinical studies in this regard. Meanwhile, he's gratified that a rare malignancy, hitherto “not prioritized by pharma when it comes to CAR T,” may soon join the list of blood cancers for which this powerful cellular therapy is indicated.

“I think every CD19 CAR T out there should be evaluated in MCL, even if it takes longer for patient accrual,” he says. “We've never been closer to a cure.” –Alissa Poh