Locally manufactured point-of-care CD19 chimeric antigen receptor T-cell therapy for paediatric relapsed/refractory B-cell acute lymphoblastic leukaemia: a single-centre feasibility experience.
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BACKGROUND: The high cost of commercial CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy for relapsed/refractory B-cell acute lymphoblastic leukaemia (B-ALL) is prohibitive for many centres and families worldwide. It is imperative to develop a cost-effective, high-quality local manufacturing system to make CAR-T a financially feasible point-of-care (POC) production option for patients. OBJECTIVE AND STUDY DESIGN: This was a single-centre, open-label, non-randomised phase II clinical trial aimed at evaluating the efficacy and safety of the locally manufactured autologous anti-CD19 CAR-T cells, generated using the CliniMACS Prodigy system, in the treatment of relapsed/refractory B-ALL. The production efficiency, efficacy, and toxicity of CAR-T therapy were evaluated. RESULTS: A total of 6 patients were recruited, including 3 male and 3 female patients. Five patients were recruited upon first relapse, while one was recruited upon second relapse. Two patients had central nervous system involvement upon relapse, as determined by flow cytometry (CNS2). The median age at CAR-T infusion was 9 years (range 4-14 years). The median time from the most recent relapse to CAR-T infusion was 5.33 months (range 4.58-5.83 months). The median percentage of blasts was 5% (range 3%-93%) in bone marrow before CAR-T infusion. All patients received intravenous cyclophosphamide 1,000 mg/m2 and fludarabine 120 mg/m2 for lymphodepletion. The median cell dose was 2.67 × 106 CAR-positive viable T cells/kg (range 2.3-2.95 × 106/kg). The median transduction efficiency was 42.86% (range 33.89%-62.1%) and the median viability of CD3+ cells was 96.22% (range 95.61%-96.78%). The median viral copy number was 2.03 (range 1.72-2.48). All products were intact with no visible damage or leakage. The median filled volume per bag was 28.96 mL (range 15.8-64.01), with a median number of viable CAR-T cells of 76 × 106 cells (range 47 to 174 × 106 cells) and a median concentration of viable CAR-T cells of 2.71 × 106/mL (range 2.41-2.99 × 106/mL). No aggregates or endotoxins (<0.500 EU/mL) were detected in any of the products. Tests for bacterial growth and mycoplasma by quantitative PCR (qPCR) were all negative. Five patients experienced grade 1 cytokine release syndrome (CRS), while one patient experienced grade 3 CRS. CRS occurred at a median of 1.5 days (range 0-6 days) after infusion and resolved by a median of 6.5 days (range 5-16 days) after infusion with the use of a median of 3 doses (range 1-8 doses) of tocilizumab. At a median follow-up of 9 months, all patients remained in remission. The median progression-free survival was not reached. All patients were administered intravenous immunoglobulin replacement every 4 weeks after CAR-T infusion. CONCLUSION: Locally manufactured POC CAR-T may be a feasible option for providing potentially safe, timely, and cost-effective therapy for B-ALL upon first relapse, based on preliminary Hong Kong data from a small number of patients. Further validation in larger studies is recommended to validate scalability, long-term persistence, and cost-effectiveness.