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Background: CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown remarkable efficacy in treating relapsed or refractory pediatric B-lineage acute lymphoblastic leukemia (B-ALL). However, poor results are obtained when the same product is reused in patients who relapse after CAR-T. Therefore, there is a need to explore the safety and efficacy of co-administration of CD19- and CD22-targeted CAR-T as a salvage second CAR-T therapy (CART2) in B-ALL patients who relapse after their first CD19 CAR-T treatment (CART1)., Methods: In this study, we recruited five patients who relapsed after CD19-targeted CAR-T. CD19- and CD22-CAR lentivirus-transfected T cells were cultured separately and mixed before infusion in an approximate ratio of 1:1. The total dose range of CD19 and CD22 CAR-T was 4.3 × 10 6 -1.5 × 10 7 /kg. Throughout the trial, we evaluated the patients' clinical responses, side effects, and the expansion and persistence of CAR-T cells., Results: After CART2, all five patients had minimal residual disease (MRD)-negative complete remission (CR). The 6- and 12-month overall survival (OS) rates were 100%. The median follow-up time was 26.3 months. Three of the five patients bridged to consolidated allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CART2 and remained in MRD-negative CR at the cut-off time. In patient No. 3 (pt03), CAR-T cells were still detected in the peripheral blood (PB) at 347 days post-CART2. Cytokine release syndrome (CRS) only occurred with a grade of ≤ 2, and no patients experienced symptoms of neurologic toxicity during CART2., Conclusions: Mixed infusion of CD19- and CD22-targeted CAR-T cells is a safe and effective regimen for children with B-ALL who relapse after prior CD19-targeted CAR-T therapy. Salvage CART2 provides an opportunity for bridging to transplantation and long-term survival., Trial Registration: Chinese Clinical Trial Registry, ChiCTR2000032211. Retrospectively registered: April 23, 2020., (© 2023. The Author(s).)

Purpose: We determined the safety and efficacy of coadministration of CD19- and CD22-chimeric antigen receptor (CAR) T cells in patients with refractory disease or high-risk hematologic or isolated extramedullary relapse of B-acute lymphoblastic leukemia., Patients and Methods: This phase II trial enrolled 225 evaluable patients age ≤ 20 years between September 17, 2019, and December 31, 2021. We first conducted a safety run-in stage to determine the recommended dose. After interim analysis of the first 30 patients treated (27 at the recommended dose) showing that the treatment was safe and effective, the study enrolled additional patients according to the study design., Results: Complete remission was achieved in 99.0% of the 194 patients with refractory leukemia or hematologic relapse, all negative for minimal residual disease. Their overall 12-month event-free survival (EFS) was 73.5% (95% CI, 67.3 to 80.3). Relapse occurred in 43 patients (24 with CD19 + /CD22 + relapse, 16 CD19 - /CD22 + , one CD19 - /CD22 - , and two unknown). Consolidative transplantation and persistent B-cell aplasia at 6 months were associated with favorable outcomes. The 12-month EFS was 85.0% (95% CI, 77.2 to 93.6) for the 78 patients treated with transplantation and 69.2% (95% CI, 60.8 to 78.8) for the 116 nontransplanted patients ( P = .03, time-dependent covariate Cox model). All 25 patients with persistent B-cell aplasia at 6 months remained in remission at 12 months. The 12-month EFS for the 20 patients with isolated testicular relapse was 95.0% (95% CI, 85.9 to 100), and for the 10 patients with isolated CNS relapse, it was 68.6% (95% CI, 44.5 to 100). Cytokine release syndrome developed in 198 (88.0%) patients, and CAR T-cell neurotoxicity in 47 (20.9%), resulting in three deaths., Conclusion: CD19-/CD22-CAR T-cell therapy achieved relatively durable remission in children with relapsed or refractory B-acute lymphoblastic leukemia, including those with isolated or combined extramedullary relapse., [Media: see text]., Competing Interests: Jun J. YangResearch Funding: Takeda (Inst) Wing LeungEmployment: Miltenyi Biotec Ching-Hon PuiLeadership: Adaptive BiotechnologiesHonoraria: NovartisConsulting or Advisory Role: Adaptive BiotechnologiesResearch Funding: National Cancer InstituteNo other potential conflicts of interest were reported.

Purpose: Anti-CD19 chimeric antigen receptor T-cell immunotherapy (19CAR-T) has achieved impressive clinical results in adult and pediatric relapsed/refractory (r/r) B-lineage acute lymphoblastic leukemia (B-ALL). However, the application and effect of CAR-T therapy in B-ALL patients with extramedullary relapse are rarely issued even disqualified in some clinical trials. Here, we examined the efficacy of 19CAR-T in patients with both bone marrow and extramedullary involvement., Materials and Methods: CAR-T cells were generated by transfection of primary human T lymphocytes with a lentiviral vector expressing anti-CD19 single chain antibody fragments (scFvs) with the cytoplasmic domains of 4-1BB and CD3ζ, and used to infuse patients diagnosed as having r/r B-ALL with extramedullary origination. Clinical responses were evaluated by the use of bone marrow aspiration, imaging, and flow cytometry., Results: Eight patients received 19CAR-T infusion and all attained complete remission (CR). Only one patient was bridged to hematopoietic stem cell transplantation (HSCT). Although three patients relapsed after infusion, they received 19/22CAR-T infusion sequentially and attained a second remission. To date, five patients are in continuous CR and all eight patients are still alive. The mean follow-up time was 21.9 months, while the 24-month estimated event-free survival is 51.4%., Conclusion: 19CAR-T therapy can lead to clinical remission for extramedullary relapsed pediatric B-ALL patients. However, the problem of CD19+ relapses after CAR-T remained to be solved. For patients relapsing after CAR-T, a second CAR-T therapy creates another opportunity for remission for subsequent HSCT.

Background: TCF3-HLF positive leukemia represents a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL), characterized by a high treatment failure rate despite intensive treatment and hematopoietic stem cell transplantation (HSCT)., Patients and Methods: Four consecutive children with TCF-HLF3-positive B-ALL who were refractory or relapsed with initial chemotherapy were treated with CD19-specific or combined CD19-and CD22-specific chimeric antigen receptor T-cell therapy (19/22 CAR-T) after conditioning regimen with fludarabine and cyclophosphamide. Clinical features, treatment responses, toxicity, and outcomes were analyzed retrospectively., Results: Four patients received 18.0, 6.0, 5.0, and 7.4 × 10 6 CAR-T cells per kilogram and developed grade I, III, II, and III cytokine release syndrome, respectively. They all achieved minimal residual disease-negative complete remission (CR). Two of them (patients 1 and 3) underwent haploid HSCT afterward. Patient 1 relapsed after 7.2 months of transplantation and received donor-derived 19/22 CAR-T cell infusion. He had CR2 after he experienced grade II cytokine release syndrome of the second CAR-T and underwent umbilical cord blood transplantation. Unfortunately, this child died of severe lung graft versus host disease 8.4 months after the second transplantation. Patients 2 and 4 experienced reversible neurotoxicity and had a persistent clinical response to CAR-T cells for 13.8 and 6.8 months, respectively, without HSCT. Patient 3 is in continuous CR for 10.6 months until now., Conclusion: CAR-T cells can effectively treat relapsed/refractory TCF3-HLF-positive childhood B-ALL with acceptable toxicity, which could be a new treatment option for this subtype compared with chemotherapy or HSCT., (Copyright © 2021. Published by Elsevier Inc.)