A guide to manufacturing CAR T cell therapies

Vormittag, Philipp; Gunn, Rebecca; Ghorashian, Sara; Veraitch, Farlan

doi:10.1016/j.copbio.2018.01.025

Cited by 291 publications

(276 citation statements)

References 87 publications

(83 reference statements)

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“…Furthermore, we have found that this manufacturing change can also increase the potency of the resulting CAR T cell product 40 . Guidelines for the development of commercial CAR cell products have been developed and are likely to evolve as our knowledge and experience grow 41,42 .…”

Section: Wwwnaturecom/nrclinoncmentioning

confidence: 99%

Mechanisms of resistance to CAR T cell therapy

2019

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Section: Wwwnaturecom/nrclinoncmentioning

confidence: 99%

Mechanisms of resistance to CAR T cell therapy

2019

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“…This issue is compounded by the observation that many academic and commercial vector manufacturing facilities were designed with scales necessary to support ex-vivo programs in mind [102]. Furthermore, wait times to access such manufacturing facilities appear to be increasing [103]—in part due to spectacular successes achieved with immuno-oncology ex-vivo gene/cell therapy approaches such as chimeric antigen receptor T-cell based therapies [104]. To facilitate the translational success emerging with in-vivo gene transfer, considerable focus must be brought to bear on the cost-of-goods associated with manufacturing vectors.…”

Section: Expert Opinionmentioning

confidence: 99%

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

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Introduction: Ex-vivo gene therapy has had significant clinical impact over the last couple of years and in-vivo gene therapy products are being approved for clinical use. Gene therapy and gene editing approaches have huge potential to treat genetic disease and chronic illness. Areas covered: This article provides a review of in-vivo approaches for gene therapy in the lung and liver, exploiting non-viral and viral vectors with varying serotypes and pseudotypes to target-specific cells. Antibody responses inhibiting viral vectors continue to constrain effective repeat administration. Lessons learned from ex-vivo gene therapy and genome editing are also discussed. Expert opinion: The fields of lung and liver in-vivo gene therapy are thriving and a comparison highlights obstacles and opportunities for both. Overcoming immunological issues associated with repeated administration of viral vectors remains a key challenge. The addition of targeted small molecules in combination with viral vectors may offer one solution. A substantial bottleneck to the widespread adoption of in-vivo gene therapy is how to ensure sufficient capacity for clinical-grade vector production. In the future, the exploitation of gene editing approaches for in-vivo disease treatment may facilitate the resurgence of non-viral gene transfer approaches, which tend to be eclipsed by more efficient viral vectors.

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“…Nevertheless, the production of primary T-cells has often been considered optimal under static conditions despite the cells being a suspension cell type by nature, with many clinical and small-scale processes opting to employ static T-flask or sterile culture bags for cell production (Vormittag, Gunn, Ghorashian, & Veraitch, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…To overcome these challenges, clinical research and commercial groups have used the use of rocking motion bioreactor systems (e.g., GE Healthcare's WAVE bioreactor or BIOSTAT RM from Sartorius Stedim Biotech), which improve the homogeneity of the culture, sampling and implementation of process control strategies (Marsh et al, 2017;Vormittag et al, 2018). To overcome these challenges, clinical research and commercial groups have used the use of rocking motion bioreactor systems (e.g., GE Healthcare's WAVE bioreactor or BIOSTAT RM from Sartorius Stedim Biotech), which improve the homogeneity of the culture, sampling and implementation of process control strategies (Marsh et al, 2017;Vormittag et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Establishing the scalable manufacture of primary human T‐cells in an automated stirred‐tank bioreactor

Costariol

Rotondi

Amini

et al. 2019

Biotech & Bioengineering

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Advanced cell and gene therapies such as chimeric antigen receptor T-cell immunotherapies (CAR-T), present a novel therapeutic modality for the treatment of acute and chronic conditions including acute lymphoblastic leukemia and non-Hodgkin lymphoma. However, the development of such immunotherapies requires the manufacture of large numbers of T-cells, which remains a major translational and commercial bottleneck due to the manual, small-scale, and often static culturing systems used for their production. Such systems are used because there is an unsubstantiated concern that primary T-cells are shear sensitive, or prefer static conditions, and therefore do not grow as effectively in more scalable, agitated systems, such as stirred-tank bioreactors, as compared with T-flasks and culture bags.In this study, we demonstrate that not only T-cells can be cultivated in an automated stirred-tank bioreactor system (ambr ® 250), but that their growth is consistently and significantly better than that in T-flask static culture, with equivalent cell quality.Moreover, we demonstrate that at progressively higher agitation rates over the range studied here, and thereby, higher specific power inputs (P/M W kg −1 ), the higher the final viable T-cell density; that is, a cell density of 4.65 ± 0.24 × 10 6 viable cells ml −1 obtained at the highest P/M of 74 × 10 −4 W kg −1 in comparison with 0.91 ± 0.07 × 10 6 viable cells ml −1 at the lowest P/M of 3.1 × 10 −4 W kg −1 . We posit that this improvement is due to the inability at the lower agitation rates to effectively suspend the Dynabeads ® , which are required to activate the T-cells; and that contact between them is improved at the higher agitation rates. Importantly, from the data obtained, there is no indication that T-cells prefer being grown under static conditions or are sensitive to fluid dynamic stresses within a stirred-tank bioreactor system at the agitation speeds investigated. Indeed, the opposite has proven to be the case, whereby, the cells grow better under higher agitation speeds while maintaining their quality. This study is the first demonstration of primary T-cell ex vivo manufacture activated by Dynabeads ® in an automated stirred-tank bioreactor system such as the ambr ® 250 and the findings have the potential to be applied to multiple other cell candidates for advanced therapy applications. K E Y W O R D Sbioprocessing, immunotherapy, manufacture, scale-up, stirred-tank bioreactor, T-cell

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A guide to manufacturing CAR T cell therapies

Cited by 291 publications

References 87 publications

Mechanisms of resistance to CAR T cell therapy

Mechanisms of resistance to CAR T cell therapy

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Establishing the scalable manufacture of primary human T‐cells in an automated stirred‐tank bioreactor

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