Manufacturing commercial axicabtagene ciloleucel for european patients: A 2-year retrospective analysis
Authors: L. V. Van De Wie, D. Hallard, S. Ensari, D. Rangel, A. Dumont, E. Granados, D. Tonelli
Journal: HemaSphere (2021)

Background: Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, was granted marketing authorization by the European Commission on August 28, 2018 for use in adults with relapsed/refractory diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after ≥2 prior lines of systemic therapy. Aims: To describe 2 years of post-marketing authorization experience in manufacturing from a United States site and supplying commercial axi-cel lots in European countries and Israel. Methods: From apheresis material collected at a qualified treatment center, peripheral blood mononuclear cells (PBMCs) were manufactured and cryopreserved in The Netherlands and then shipped to the United States (El Segundo, CA) to continue manufacturing. If additional apheresis was needed, the first apheresis was considered for each patient, and is subsequently referred to as that patient's lot. The finished product lot was shipped back to The Netherlands for European Qualified Person (QP) release and then sent to the hospital for administration to the patient. Results: From first apheresis after marketing authorization, September 6, 2018, until September 5, 2020, 1074 patients were included on the Kite Konnect. website and provided apheresis material for axi-cel manufacturing. The median and mean turnaround times from apheresis to QP release were 25 days and 26.2 days, respectively. The median and mean times from apheresis to shipment were 29 days and 31.5 days, respectively. Despite the transatlantic air travel disruption due to the COVID- 19 pandemic, the median turnaround time from apheresis to QP release from March 2020 to August 2020 was not affected (25 days). For those 1074 patients for whom manufacturing was started, 1040 commercial axi-cel lots (97%) were released, and 1000 (93%) were delivered, including 19 lots (1.8%) that were out of specification. Out of specification commercial axi-cel lots were released exceptionally and on physician's request based on a risk/benefit assessment according to the European Union Advanced Therapy Medicinal Product guidelines. To obtain this level of manufacturing success, a remanufacturing step was required either from frozen PBMC bags in 19 cases (1.8%) or from new apheresis in 19 cases (1.8%). In addition, 18 patients (1.7%) had batches rejected;7 patients (0.7%) had production terminated, and 9 patients (0.8%) had orders cancelled. In June 2020, a new facility in Hoofddorp, The Netherlands opened to engineer cell therapies for European patients with the objective of substantially reducing time from apheresis to QP release and to avoid transatlantic transport. Summary/Conclusion: In conclusion, the initial 2-year experience in manufacturing commercial axi-cel for European countries shows high manufacturing success, with a reliable time from apheresis to QP release (median, 25 days) and a very low percentage (1.8%) of out of specification lots released on physician's request.