Performance-enhancing drugs: design and production of redirected chimeric antigen receptor (CAR) T cells

Abstract

Performance enhancement of the immune system can now be generated through ex vivo gene modification of T cells in order to redirect native specificity to target tumor antigens. This approach combines the specificity of antibody therapy, the expanded response of cellular therapy and the memory activity of vaccine therapy. Recent clinical trials of chimeric antigen receptor (CAR) T cells directed toward CD19 as a stand-alone therapy have shown sustained complete responses in patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia. As these drug products are individually derived from a patient's own cells, a different manufacturing approach is required for this kind of personalized therapy compared with conventional drugs. Key steps in the CAR T-cell manufacturing process include the selection and activation of isolated T cells, transduction of T cells to express CARs, ex vivo expansion of modified T cells and cryopreservation in infusible media. In this review, the steps involved in isolating, genetically modifying and scaling-out the CAR T cells for use in a clinical setting are described in the context of in-process and release testing and regulatory standards.

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

“…These receptors target specific proteins found on the surface of leukaemia cells, in this case the protein CD19, which is present on B-cell leukaemias as well as on healthy B cells, but which is not found on haematopoietic stem cells (which are situated in the bone marrow) or on other tissues. 145 The activated T-cells can then attack and destroy the leukaemia B cells. Persistence of a given CAR T-cell therapy within the body is linked to the properties of the T-cell from which the cells were derived as well as the immune environment into which they are infused.…”

“…Levine et al 145 summarises the CAR T-cell process as follows: separating the processes of leukapheresis, conditioning chemotherapy and infusion from the transduction and expansion. We assumed the same separation to represent those components of care that would be provided (and funded separately) by the NHS and those that would be undertaken by the manufacturer and included within the acquisition cost of CAR T-cell therapy.…”

Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL

“…Because CD19 is the target for axicabtagene ciloleucel and several other leading CAR T cell therapies under investigation for the treatment of B cell malignancies, and CD19 is expressed on malignant and healthy B cells [58], the risk of so-called on-target, offtumor toxicity is restricted to normal B cell aplasia [51]. Patients lacking B cells after CAR T therapy may require immunoglobulin supplementation [51,59].…”

Applications and optimization of cryopreservation technologies to cellular therapeutics

“…With the recent arrival of manipulated T cell therapies, such as chimeric antigen receptor engineered (CAR ) T cells destined for autologous transfusion [64,65], cryopreservation will undoubtedly remain the important facilitatory technology in the pathways for product management, batch safety and potency validation, and, in many cases, delivery to end users. Cryopreservation has already been discussed in these terms [64] but cryo-protocol details are as yet sparsely reported and it is likely that general slow cooling regimes originally developed for HPC have been adopted.…”

“…Cryopreservation has already been discussed in these terms [64] but cryo-protocol details are as yet sparsely reported and it is likely that general slow cooling regimes originally developed for HPC have been adopted. Here also, product depletion and post-thaw potency have been reported [66].…”