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Manufacturing of patient specific novel T cell therapies using the Cocoon® Platform automated system
Get PDFEngineered T cell therapies, particularly chimeric antigen receptor T cell (CAR-T) immunotherapies, have proved effective against hematologic cancers. However, CAR-T therapies can potentiate immune responses causing cytokine release syndrome (CRS; “cytokine storm”) leading to adverse events in patients. Additionally, CAR-T has shown sporadic success in solid tumor indications. Novel therapies which activate T cells via the native T cell receptors (TCR) have shown greater tumor antigen recognition providing an alternative therapy which may prove effective against solid tumors. Utilizing novel cell immunotherapy modalities is only part of the solution as challenges remain to scale manufacturing to meet commercial demand. Scaling out commercial patient-specific cell therapy manufacturing for large populations using current methods will be expensive (cleanrooms and FTEs) and complex (logistics). Innovative manufacturing solutions will be required to manufacture patient-specific therapies in a robust and cost-effective manner. The Cocoon® Platform is one such innovation, a functionally-closed, automated, scalable cell therapy manufacturing platform. This abstract highlights a therapeutic T cell process translated from an open, manual process to the Cocoon® Platform.
During process translation, the functionally-closed Cocoon® Platform was used to automate cell seeding, activation, transduction, feeding, real-time process monitoring, washing, and final product harvest using the single-use Cocoon cassette. During process development and translation, important process parameters were identified, optimized, and programmed enabling multiple process step automation removing the need for manual intervention. For the process, 200 million CD4+ and CD8+ isolated T cells were inoculated with TransActTM activator. The following day, cells were transduced with HER-2 lentivirus vector at various multiplicities of infection (MOI). Cells were expanded with a predefined feeding strategy in media supplemented with IL-2 until final product harvest. Following harvest, cells were assessed for cell yield, viability, transduction efficiency, and VCN. T cell phenotype and functionality was assessed via flow cytometry.
The Cocoon manufacturing processes yielded 2.7 x 109 viable cells on average with viability \u3e85%. The Cocoon processes supported both CD4+ and CD8+ T cell expansion with 68% CD4+ T cells and 31% CD8+ T cells on average. The final product exhibited high T cell purity and viability (i.e. \u3e90% abTCR+ and 89% abTCR+, respectively) with transduction efficiencies varied from ~30% to \u3e65% depending on the process MOI. Vector copy number (VCN) was evaluated after each process and found to be ≤5 copies/transduced T cell.
In summary, a gene-modified T cell process was successfully translated to the Cocoon and the harvested final products met all pre-defined acceptable criteria. The Cocoon represents a tool for manufacturing cell therapies in a robust manner, while maintaining comparability, and lowering manufacturing costs via increased automation. Ultimately the Cocoon will enable and accelerate development of cell therapies to address solid tumor indications and meet a critical patient need
Computational fluid dynamic characterization of vertical-wheel bioreactors used for effective scale-up of human induced pluripotent stem cell aggregate culture
Get PDFInnovations in engineering and bioprocess development have accelerated the transition of induced pluripotent stem cell (iPSC) cultivation and use from the bench-top to large-scale clinical manufacturing. Owing to their potency, proliferation capabilities, and ability to overcome the challenges associated with traditional sources of pluripotent stem cells (PSCs), iPSCs have generated significant interest in the field of regenerative medicine for more than a decade. However, traditional bench scale methods to expand iPSCs, including petri dishes and T-flasks, are insufficient to achieve clinically relevant numbers. For iPSC treatments, cell dosages will range from 109 – 1012 cells per patient depending on the therapeutic target. To achieve the required number of cells in an effective and scalable manner, bioreactors will need to be used. Induced pluripotent stem cells (iPSCs) have proven to be extremely sensitive to the bioreactor hydrodynamic environment, making the use of suspension bioreactors to produce quality-assured cells at clinical and commercial scales very challenging. The PBS vertical-wheel (VW) bioreactor combines radial and axial flow components to produce uniform hydrodynamic force distributions, making it a promising platform to overcome the scale-up challenges associated with iPSCs.
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High-throughput affinity-resin based scale down method for T cell isolation
Get PDFT cell therapy processes may require cell selection unit operations at manufacturing. Performing these unit operations at manufacturing scale for development experiments is costly, time-consuming, and inefficient. Here we will describe development experiments for a high-throughput affinity-resin based T cell selection. This scale down platform may also be amenable for automated liquid handling systems in a sterile manner
Encapsulation of aqueous-core nanocapsules in PLLA multicompartments microparticles
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Understanding the microstructure differences in the emulsion polymerization of bio-based and oil-based C8 alkyl (meth)acrylates
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Modelling of a multizone circulating reactor for propylene polymerization: Impact of thermodynamic model
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A thermodynamic perspective on the medium dependence of propagation coefficients and reactivity ratios in radical polymerization
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Mathematical modeling for control of emulsion polymerization
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Chemical recycling of polyethylene by tandem catalytic conversion to propylene
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Measurement of exothermic reaction temperature during RMI process
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