Lentiviral vector bioprocess economics for cell and gene therapy commercialization

Comisel, Ruxandra-Maria; Kara, Bo; Fiesser, Frederick H.; Farid, Suzanne S.

doi:10.1016/j.bej.2020.107868

Cited by 42 publications

(74 citation statements)

References 99 publications

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“…The sensitivity of autologous cell therapies to scalable viral production is indicated in some cost of goods analysis, with up to 26% contribution to cost when viral titre is poor [ 26 ]. Likewise, cost per dose is further shown to be dependent on titre at harvest and the production method employed [ 27 ].…”

Section: Bioprocessing Of Lentiviral Vectorsmentioning

confidence: 99%

“…With scale up, where larger and more consistent batch sizes are desired, production transitions to bioreactors in the form of stirred tanks, rocking waves and fixed bed bioreactors with multi-layer flasks straddling the intermediate scales. In terms of efficient cost of goods production, a recent study indicates single-use stirred tanks as most cost-efficient where suspension culture is available, otherwise fixed beds offer greater savings than adherent flask culture [ 27 ]. Many upstream culture vessels have also transitioned onto single use disposables.…”

Section: Upstream Bioprocessing Of Lentiviral Vectorsmentioning

confidence: 99%

“…USD enables whole-bioprocess assessment because of the small amount of material required to perform the analysis. Lastly, as part of the whole-bioprocess analysis of the production of LVs, incorporating a process economic analysis would be beneficial as it could demonstrate the economic viability of bioprocess options [ 27 ].…”

Section: Whole-bioprocess Assessment Of LV Productionmentioning

confidence: 99%

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Lentiviral Vector Bioprocessing

Perry

Rayat

2021

Viruses

110

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Lentiviral vectors (LVs) are potent tools for the delivery of genes of interest into mammalian cells and are now commonly utilised within the growing field of cell and gene therapy for the treatment of monogenic diseases and adoptive therapies such as chimeric antigen T-cell (CAR-T) therapy. This is a comprehensive review of the individual bioprocess operations employed in LV production. We highlight the role of envelope proteins in vector design as well as their impact on the bioprocessing of lentiviral vectors. An overview of the current state of these operations provides opportunities for bioprocess discovery and improvement with emphasis on the considerations for optimal and scalable processing of LV during development and clinical production. Upstream culture for LV generation is described with comparisons on the different transfection methods and various bioreactors for suspension and adherent producer cell cultivation. The purification of LV is examined, evaluating different sequences of downstream process operations for both small- and large-scale production requirements. For scalable operations, a key focus is the development in chromatographic purification in addition to an in-depth examination of the application of tangential flow filtration. A summary of vector quantification and characterisation assays is also presented. Finally, the assessment of the whole bioprocess for LV production is discussed to benefit from the broader understanding of potential interactions of the different process options. This review is aimed to assist in the achievement of high quality, high concentration lentiviral vectors from robust and scalable processes.

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Section: Bioprocessing Of Lentiviral Vectorsmentioning

confidence: 99%

Section: Upstream Bioprocessing Of Lentiviral Vectorsmentioning

confidence: 99%

Section: Whole-bioprocess Assessment Of LV Productionmentioning

confidence: 99%

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Lentiviral Vector Bioprocessing

Perry

Rayat

2021

Viruses

110

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“…Zolgensma's AAV upstream manufacturing process relies on an iCELLis® fixed bed bioreactor (FBR) adherent platform. iCEL-Lis FBR platform has been cited as the 'most cost-effective option' for adherent cell culture [7], and has been used as a commercially viable solution without the need to switch to a suspension platform. There is extensive data available to demonstrate how one may scale a, say, 48L Cell Factories based process to a 200L iCELLis® FBR without changing critical quality attributes (CQAs) of the product [8].…”

Section: The Case For Adherent Based Platformsmentioning

confidence: 99%

Adherent versus suspension based platforms: what is the near future of viral vector manufacturing?

Baghirzade¹

2021

Cell and Gene Therapy Insights

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The first sentence of Tolstoy's opus Anna Karenina starts by declaring that "All happy families are alike; each unhappy family is unhappy in its own way." Popularized as 'Anna Karenina principle', and applied in multiple scientific and social disciplines, the concept suggests that successful endeavors all share a common set of main traits, while there are many routes to misery if there is a deficiency in any of the key attributes. Paraphrasing Tolstoy, while successful manufacturing platforms are all alike (e.g. with regards to titers and yield), every unsuccessful manufacturing platform is deficient in its own way."Therapeutics developers are searching for a viable viral vector manufacturing platform as the industry is at the inflection point. Paraphrasing Tolstoy, while successful manufacturing platforms are all alike, every unsuccessful manufacturing platform is deficient in its own way."

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“…Furthermore, virus production is a laborious procedure requiring regulatory approval for preclinical research in many countries. Moreover, the costs associated with the production of clinical grade retroviruses are a limiting factor for the translation of new CAR T cell therapies 16 .…”

Section: Introductionmentioning

confidence: 99%

Fast, Efficient and Virus-Free Generation of TRAC-Replaced CAR T Cells

Kath

Thommandru

et al. 2021

SSRN Journal

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Chimeric Antigen Receptor (CAR) redirected T cells are a potent treatment option for certain hematological malignancies. Recently, site-specific insertion of CARs into the T cell receptor (TCR) alpha constant (TRAC) locus using gene editing and adeno-associated viruses was shown to generate CAR T cells with improved functionality over their retrovirally transduced counterparts. However, the development of viruses for gene transfer is complex and associated with extensive costs at early clinical stages. Here, we provide an economical and virus-free method for efficient CAR insertion into the TRAC locus of primary human T cells via CRISPR-Cas mediated homology-directed repair (HDR). While the toxicity induced by transfected double-stranded template (donor) DNA was not fully prevented by pharmacological means, the combination of DNA-sensor inhibitors and HDR enhancers resulted in highly efficient gene editing with TCR-to-CAR replacement rates reaching up to 68%. The resulting TCR-deficient CAR T cells show antigen-specific cytotoxicity and cytokine production in vitro. Our GMP-compatible non-viral platform technology lays the foundation for clinical trials and fast-track generation of novel CAR T cells applicable for autologous or allogeneic off-the-shelf use..

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Lentiviral vector bioprocess economics for cell and gene therapy commercialization

Cited by 42 publications

References 99 publications

Lentiviral Vector Bioprocessing

Lentiviral Vector Bioprocessing

Adherent versus suspension based platforms: what is the near future of viral vector manufacturing?

Fast, Efficient and Virus-Free Generation of TRAC-Replaced CAR T Cells

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