Bispecific CD19/CD22 CAR T Cells Active in Pediatric Relapsed ALL

Haneen Shalabi, DO

Treatment with CD19/22 chimeric antigen receptor (CAR) CAR T cells induced a promising response in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), according to phase I findings presented at the virtual 2020 American Association for Cancer Research Annual Meeting.¹

Lead author Haneen Shalabi, DO, added that the novel humanized bispecific CD19/CD22 CAR T-cell construct appeared to be well-tolerated in this patient population.

"The early experience with the bispecific CD19/CD22 CAR T cells demonstrates clinical activity with reversible CRS [cytokine release syndrome] and limited neurotoxicity," said Shalabi, an assistant research physician in the pediatric oncology branch at the National Cancer Institute's Center for Cancer Research. "Responses were seen in all CAR-naïve patients, and responses were dose-dependent with increased CAR expansion in high-burden disease."

At present, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (axi-cel, Yescarta), both of which target CD19, are the only CAR T-cell therapies approved for children with relapsed/refractory ALL. Although cure rates for pediatric ALL are as high as 90%, up to 20% of patients are refractory to treatment or experience at least 1 relapse.²

Shalabi et al developed a novel bivalent, bispecific CAR targeting both CD19 and CD22. Investigators hypothesized that targeting both antigens would reduce the risk for antigen loss, which causes disease relapse.

Investigators recruited 15 patients into the phase I dose escalation trial (NCT03448393). Thirteen patients have been treated so far. The median age for all patients is 19.6 years (range, 5.4-28.5). Four patients were treated at dose level 1 (3 x 10⁵ transduced CAR T-cell/kg), 4 were treated at dose level 2 (1 x 10⁶ transduced CAR T-cell/kg), and 5 were treated at dose level 3 (3 x 10⁶ transduced CAR T-cell/kg).

Five of 12 evaluable patients had complete responses (CR), all at dose levels 2 or 3. Furthermore, all 5 were negative for minimal residual disease. Four of those 5 patients were CAR-naïve and 8 of 12 had clearance of bone marrow disease. Four patients had partial responses, Shalabi said.

Shalabi said all responders displayed CAR T cell expansion, but persistence was limited. The median peak percentage of CAR T cells in the peripheral blood, was 7% (range, 0-55). At day 28, the median peak percentage in the bone marrow was 1.3% (range, 0-22).

As measured by flow cytometry, investigators detected CAR T cells in the peripheral blood out to a median of 45.6 days (range, 13-87). PCR data is pending.

"Limited CAR persistence is likely contributory to antigen positive relapses," Shalabi said. "Longer follow up and a larger cohort is needed to assess the dual functionality of this CAR."

So far, 2 of 5 patients have relapsed with CD19/CD22-positive disease. One relapsed after transplant, 265 days post-infusion. The other relapsed 123 days post-infusion.

Shalabi said 3 patients remain in remission at a median of 7 months post-infusion (range, 1-8 months). One patient underwent a first hematopoietic cell transplant (HCT) after restaging studies, 1 is in ongoing CR at 7 months without interval therapy, and 1 is in ongoing CR at 6 weeks post-infusion and awaiting a second HCT.

Agents targeting CD19 are often associated with CRS and neurotoxicity, leading investigators to look for safer options. In a 2018 analysis of the landmark ELIANA trial (NCT02435849) that led to the FDA approval of tisagenlecleucel, 46% of patients experienced grade 3/4 CRS and 47% patients were admitted to the intensive care unit for management of CRS.³

In the Shalabi study, 13 patients were evaluable for safety. Six (46%) patients experienced CRS. However, CRS was grade 3 or higher in only 2 (15.4%) patients, both of whom were treated at dose level 2. Three patients, 2 at dose level 2, and 1 at dose level 3, received tocilizumab for CRS. Only 1 patient, treated at dose level 3, developed neurotoxicity. That patient received tocilizumab for CRS and steroids for neurotoxicity.

"Toxicities were reversible in all patients," Shalabi said.

References

1. Shalabi H, Yates B, Shahani S, et al. Safety and efficacy of CD19/CD22 CAR T cells in children and young adults with relapsed/refractory ALL. Presented at: 2020 AACR Virtual Annual Meeting; April 27-28, 2020. Abstract CT051.
2. Forsberg MH, Das A, Saha K, Capitini CM. The potential of CAR T therapy for relapsed or refractory pediatric and young adult B-cell ALL. Ther Clin Risk Manag. 2018;14:1573—1584. doi:10.2147/TCRM.S146309
3. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018; 378:439-448. doi:10.1056/NEJMoa1709866

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