Delivery of Obecabtagene Autoleucel (obe-cel, AUTO1) for the FELIX Pivotal Study Demonstrating Robust Cell Processing, Robust Release Testing, and Reliable Logistics, Together with Readiness for Sustainable Patient (pt) Care

Background: Obe-cel is an autologous chimeric antigen receptor (CAR) T cell product whose CD19 binding domain has a unique fast off-rate and was designed for improved safety and persistence over existing CD19 CAR T therapies. Successful CAR T therapy relies on a rapid and effective end-to-end process. The challenge for product manufacturing is twofold: first, pts with high tumor burden can have T cells that are highly differentiated and exhausted; second, pts with leukemic cells in circulation have apheresis containing a substantial proportion of leukemic cells that require removal before manufacture can start. Having robust, reliable manufacturing, testing, logistics processes, and teams that are able to provide a consistent CAR T product is key to achieving timely vein-to-certification/vein-to-delivery (V2C/V2D) targets. This abstract reports on the manufacturing, quality control (QC) and logistics processes set up for the FELIX study, and the impact of on-study optimization for scale up of production.

Methods: The FELIX clinical study design required manufacturing, testing and logistics processes that could support a global, multicenter study with a target infusion of ~90 pts. The key elements were: 1) manufacturing and testing location: obe-cel was manufactured in Stevenage, UK, chosen because of proximity to a major international airport (London Heathrow) that provides logistics access to Europe and the US, and the ability to leverage existing knowledge and talent; 2) manufacturing process: manufacturing was carried out 7 days/week, was highly automated with mainly closed-system processing, using a Miltenyi Biotec Prodigy ® (https://www.miltenyibiotec.com), 3) analytical procedures: QC procedures, including measuring biological activity and sterility testing, were carried out in-house to reduce turnaround time (TAT); 4) logistics: TAT was minimized and reliability improved by establishing primary and secondary routes plus turnkey contingency plans with courier and charter flight options 5) targets: V2C (time from leukapheresis to quality release) and V2D (time from leukapheresis to delivery of product to the hospital) of ~23 and ~25 days, respectively, for the FELIX study.

Results: Between Jul 2021 and Dec 2022 (FELIX Phase II Cohort A), the 32 clinical sites for FELIX in the US, UK and Spain were all supplied obe-cel from the UK. Median V2C and V2D times were 21 and 24 days, respectively. Despite the median leukemic B-cell content in apheresis being 21% (range 0-97%) and the median CD3+ T cell content being 13% (range 1-91%), 96% of manufactured obe-cel batches reached their target dose of 410 x 10 ⁶ CAR T cells. From apheresis to product the median (range) percentage of naïve T cells increased from 20% (1-73%) to 31% (2-74%) while the medians for T _CM and T _EM remained unchanged at 13% to 13% and 19% to 17%, respectively, and the median TEMRA content decreased from 37% (range 4-93%) to 31% (range 5-90%), indicating that the manufacturing process managed to drive towards a less differentiated T cell phenotype in the final drug product. Transduction rates were consistently high with a median of 70% (range 14-87%). In the morphological Phase II Cohort A of the FELIX study, 112 pts were leukapheresed and 94 (84%) were dosed. All leukapheresis collections and cell product deliveries were executed successfully and with the expected quality, despite the challenges posed by the COVID-19 pandemic. In addition, US international airline flights decreased by 43 % (US Dept of Transportation, Bureau of Transportation Statistics; July 2023) compared with pre COVID-19 pandemic, but sample collection and product delivery were successfully maintained, with no batches impacted. Maintaining consistently short QC and release times were driven by streamlined analytical strategy and batch records.

Conclusions: The FELIX study successfully demonstrated the robust operability of obe-cel manufacturing, QC and logistics processes, meeting target V2C and V2D. All apheresis starting material successfully processed despite the multitude of constraints posed by the COVID-19 pandemic. Further optimization and improvements made during the study increased reliability, consistency and precision of the manufacturing process, and supported the development of a new obe-cel manufacturing facility with greater production capacity that aims to achieve a ≥95% manufacturing success rate with ≤15-day V2C times.