Targeting CD19–CD22 Aids Younger Patients with ALL

Treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 and CD22 appears safe and shows preliminary signs of efficacy in children and younger adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), according to findings from a phase I trial.

Although the majority of these patients recover with standard therapy, up to 20% relapse or become refractory to therapy. The only CAR T-cell therapies approved for children and young adults are tisagenlecleucel (Kymriah; Novartis) and axicabtagene ciloleucel (Yescarta; Gilead), both of which target only CD19. In designing the CAR, researchers hypothesized that bispecific targeting would diminish the risk of antigen loss—a cause of CAR T-cell therapy nonresponse or relapse.

“How do you treat that even more difficult-to-treat patient population?” asks Aimee Talleur, MD, of St. Jude Children's Research Hospital in Memphis, TN. “Dual targeting is a way to maybe do that.”

In the trial, thirteen patients ranging from 3 to 30 years old, many of whom had received prior CD19- or CD22-targeted therapies, including CAR T-cell therapies, were treated, reported Haneen Shalabi, DO, of the NCI, who presented the findings at the American Association for Cancer Research (AACR) Virtual Annual Meeting I in April. Of the 12 patients evaluable for efficacy, five (four of whom were CAR therapy–naïve) responded to treatment, and all responses were minimal residual disease–negative complete remissions. Additionally, some of the six patients who had extramedullary disease had responses outside the central nervous system—for example, one patient's breast mass responded to treatment.

Although CAR T-cell expansion was seen in all responders, cellular persistence was limited, Shalabi reported. The median persistence of CAR T cells was 45.6 days. Three patients remained in remission for a median duration of 7 months, but the other two responders relapsed with CD19⁺CD22⁺ disease, possibly because the number of CAR T cells diminished too greatly over time.

“The persistence data does not mean that their product can't be effective,” Talleur says. She noted that modifying the CAR construct or combining CAR T-cell therapy with other treatments may yield longer responses.

In addition to demonstrating signs of efficacy, the trial met its primary endpoint of safety and manageable adverse events: Most study participants tolerated the treatment well, and toxicities were reversible in all cases. Although six patients experienced cytokine release syndrome, it was relatively mild (grade 1 or 2) in four of them and resolved with the IL6 inhibitor tocilizumab (Actemra; Roche) in the other two. “We have noted ... that higher-burden disease is what is predictive of higher-burden cytokine release syndrome,” Shalabi said.

A larger trial with longer follow-up will be needed, especially given the low average persistence of the CAR T cells, and Shalabi highlighted a desire to test an additional dose level or combine the treatment with immune checkpoint blockade in some patients, particularly those who appear less likely to respond, such as those who have received prior CAR treatment.

“This study highlights the significant opportunity of working to learn more about those patients who had already had CAR or have extramedullary disease,” Talleur comments. Findings from these patients could help inform additional studies—perhaps in solid tumors as well as in blood cancers. –Nicole Haloupek