Global Manufacturing of CAR T Cell Therapy

Abstract

Immunotherapy using chimeric antigen receptor-modified T cells has demonstrated high response rates in patients with B cell malignancies, and chimeric antigen receptor T cell therapy is now being investigated in several hematologic and solid tumor types. Chimeric antigen receptor T cells are generated by removing T cells from a patient's blood and engineering the cells to express the chimeric antigen receptor, which reprograms the T cells to target tumor cells. As chimeric antigen receptor T cell therapy moves into later-phase clinical trials and becomes an option for more patients, compliance of the chimeric antigen receptor T cell manufacturing process with global regulatory requirements becomes a topic for extensive discussion. Additionally, the challenges of taking a chimeric antigen receptor T cell manufacturing process from a single institution to a large-scale multi-site manufacturing center must be addressed. We have anticipated such concerns in our experience with the CD19 chimeric antigen receptor T cell therapy CTL019. In this review, we discuss steps involved in the cell processing of the technology, including the use of an optimal vector for consistent cell processing, along with addressing the challenges of expanding chimeric antigen receptor T cell therapy to a global patient population.

Keywords: T lymphocytes; chimeric antigen receptor; global regulatory environment; lentiviral vector; manufacturing.

Figure 1

Leukapheresis and T Cell Isolation After a sufficient number of leukocytes have been harvested from the patient’s blood via leukapheresis, the anticoagulants in the leukapheresis buffer are washed out of the product and the cells are concentrated by counterflow centrifugal elutriation, which separates cells by size and density. ^aHaemonetics Corporation.

Figure 2

T Cell Culture and Transduction The T cells are activated using aAPCs, transduced with the CAR-encoding viral vector, and expanded to large numbers in a bioreactor. After expansion, the cells are washed, concentrated, and cryopreserved. aAPC, artificial antigen-presenting cell; CAR, chimeric antigen receptor. ^aGE Healthcare Life Sciences. ^bHaemonetics Corporation.

Figure 3

The Lentiviral Vector Manufactured by Oxford BioMedica Ltd. Undergoes Several Rounds of Filtration and Testing to Ensure that a High-Quality Product with Minimal Variability Is Produced The process has been designed and optimized to manufacture vector in a series of multiple sub-batches. This approach relies on a purification and formulation step prior to cryopreservation and a subsequent hold at ≤−70°C. Specific sub-batches are then selected for final aseptic processing, which is completed in a single day. QA, quality assurance; QC, quality control; QP, qualified person. ^aMerck KGaA.

Figure 4

Transition to Commercial Manufacturing As CAR T cell therapies transition from flexible processes at single academic institutions to highly controlled processes that can be implemented across many collection, manufacturing, and treatment sites, the coordination among these sites will be crucial to ensure that the material is handled correctly and patients are scheduled appropriately.