Peer-reviewed article
CD19/CD22 bivalent CAR T cells in children, adolescents and young adults with B-ALL: final phase 1 trial results.
Silbert SK, Gava F, Yates B, Rankin AW, Rocco JM et al. ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This is a clinical trial report on a novel CAR T-cell therapy for children and young adults with B-cell acute lymphoblastic leukemia. The trial tested a bivalent CD19/CD22 CAR T-cell construct in 28 patients aged 3-39 years. The therapy achieved complete remission in 89% of patients with a manageable safety profile, though side effects like cytokine release syndrome occurred in most patients.
Key points
- 89.3% of patients (25/28) achieved measurable residual disease-negative complete remission
- Cytokine release syndrome occurred in 71.4% of patients but only 10% were grade >3 severity
- Grade 3 immune effector cell-associated neurotoxicity syndrome occurred in 10.7% (3 patients)
- 82.1% of patients proceeded to hematopoietic stem cell transplant as a bridge therapy within 51 days
- Non-response was confined to patients with non-CNS extramedullary disease
Limitations
This is a phase 1 trial with a small sample size (28 patients with B-ALL) designed primarily to assess safety and dose-escalation rather than definitive efficacy. The trial does not include a comparison group, limiting conclusions about relative effectiveness compared to standard treatments.
Abstract
Multiantigen targeting chimeric antigen receptor (CAR) T cells have emerged as a strategy to mitigate antigen escape observed after single antigen targeting therapy. Our initial experience with a bivalent CD19.22.BBζ CAR T-cell construct in children, adolescents and young adults (CAYA) with B-cell acute lymphoblastic leukemia (B-ALL) demonstrated limitations in CD22 recognition, but a tolerable safety profile and efficacy prompted further evaluation. This trial enrolled patients between the ages of 3-39 with relapsed/refractory B-ALL. Following dose-escalation, patients who enrolled at the recommended phase 2 dose (RP2D) of 3×106 transduced CAR T cells/kg constitute this report. 30 CAYA were treated at the RP2D; 28 with B-ALL and 2 with Burkitt lymphoma. Across patients with B-ALL, 20 (71.4%) patients developed cytokine release syndrome (CRS); only 2 (10%) were grade >3. Grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 3 (10.7%) patients; there were no cases of immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. Following a protocol amendment to evaluate the efficacy of siltuximab as a first-line treatment of CRS, one patient received siltuximab with full resolution of CRS after two doses without needing additional anti-cytokine-directed therapies. A measurable residual disease-negative complete remission (CR) was attained in 25 (89.3%) patients, including 6 who had neither CRS nor ICANS. 23 patients (82.1%) proceeded directly to hematopoietic stem cell transplant (HSCT) following CAR T-cell infusion within a median of 51 days (range, 45-68 days), supporting the utility of this construct as a bridge to HSCT. All three non-responders had persistent non-central nervous system (CNS) extramedullary disease (EMD), although four of seven patients with non-CNS EMD achieved a CR. Median relapse-free survival among the 25 patients achieving CR was not reached, and the median overall survival for all 28 patients was 34 months (95% CI 17 to not estimable) from infusion. This extended experience demonstrates that CD19.22.BBζ CAR T-cell therapy is safe and clinically active, particularly as a bridge to HSCT. Non-response was confined to patients with non-CNS EMD, highlighting the persistent challenge of effectively targeting EMD and informing the design of future CAR constructs.Trial registration numberNCT03448393.