Using Real-World Remanufacturing and Recollection Data to Optimize Time-to-Treatment in Patients with out-of-Specification Ciltacabtagene Autoleucel
Authors: Bowden Bob , Ciccone Daniel , Salmon James , Alegria Victoria , Kallenbach Lisa , De Braganca Kevin C 
Published: December 2023

Ciltacabtagene autoleucel (cilta-cel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor-T cell (CAR-T) immunotherapy approved for the treatment of adults with relapsed/refractory multiple myeloma. Manufacturing of cilta-cel can take approximately 4 weeks from receipt of apheresis material until release for cilta-cel infusion. Though manufacturing is a well-controlled biological production process, delays in release can occur when the final product does not meet predetermined release specifications. Such products are referred to as being out-of-specification(s) (OOS).

In the United States, OOS CAR-T products may be released for use via an exceptional release process as part of an expanded access clinical trial (NCT05346835). Additional time is needed as the process requires the prescriber's request for release, an internal safety review to assess benefit/risk, and US Food and Drug Administration (FDA) notification and/or approval. Further delays to treatment may occur if a prescriber requests to remanufacture and potentially recollect new apheresis material, attempting to obtain an in-specification product. In some instances, this increased time has resulted in clinically significant disease progression.

We reviewed and characterized the experience from discussions with prescribers regarding OOS cilta-cel over the past 18 months. Options presented to the prescriber included: (1) remanufacture using the original apheresis product, (2) recollection of new apheresis material, (3) exceptional release of the OOS cilta-cel, and (4) cancellation of the order. The outcomes for cases of remanufacturing or recollection were analyzed.

To date, remanufacturing from the initial apheresis material has been requested in 37% of OOS cases. Of these cases, 60% of remanufacturing attempts resulted in the same or worse outcomes (ie, additional OOS outcomes or worse performance on the original OOS outcomes). Recollection of new apheresis material was requested in 15% of OOS cases, either because of insufficient remaining material or concern about the impact of therapy received prior to collection. Upon recollection, 65% of these attempts resulted in the same or worse outcomes.

The reason cilta-cel was determined to be OOS varied. Of remanufacturing attempts for OOS due to a low proportion of CAR+ cells, none were successful in obtaining an in-specification product. Cases where OOS was due to low cell viability were unsuccessfully remanufactured or recollected 71% and 75% of the time, respectively, whereas OOS due to low dose was unsuccessfully remanufactured 95% of the time. On occasion, the second attempt at remanufactured OOS cilta-cel due to low dose has been combined with the OOS cilta-cel generated in the first manufacture to achieve a combined dose that meets or comes close to the specified dose range. Remanufacturing or recollection success rates were increased in cases where the root cause of the OOS was due to something inadvertent that occurred during the manufacturing process.

Our findings on remanufacturing and recollection outcomes may inform physician decisions and help optimize time-to-treatment in patients receiving cilta-cel. Additional studies (eg, NCT05347485) are underway to evaluate the safety and efficacy of OOS cilta-cel.