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250
Table 9.4 Opportunities for further innovation
Challenge Potential solutions
High operation costs Adopt innovative curriculum and interdisciplinary learning
approaches to train highly skilled workforce to meet the highly technical nature of the development and manufacturing process [103] Allogeneic, “off the shelf” therapies reduce the number of batches per patient [97]
Long vein-to-vein time Decentralized manufacturing [97, 102]
Adopt manufacturing platforms to reduce cell expansion time by increasing T-cell stemness [71, 72]
Treating solid tumors CAR NK cells, CAR macrophages, gene editing [53]
Polyclonal T-cells with enhanced stemness [73]
Improve efciency, optimizing workows
Utilizing allogeneic or iPSC-derived CAR-T cells
Potential immunotoxicity Develop highly specic antigens [104]
Cold supply chains across international borders
Automated lling and closed systems [98]
Gene editing (CRISPR, TALENs) to overcome immune rejection [99, 100].
Develop CAR “switch-offs” including apoptosis inducers and CAR anti-bodies [105, 106]
Innovative supply chain considerations [86]
A. Adeniran et al.
vector production, should have a positive impact in increasing affordability of CAR-T products. Proposed strategies for optimizing production workows are out­lined in Table9.5.
Use of molecular gene editing techniques like CRISPR or TALENs is an area of growing interest in CAR-T manufacturing, particularly in the development of allo­geneic therapies. Targeted gene editing allows for the precise removal of genes that elicit an immunosuppressive response in the host. An allogeneic anti-CD19 CAR-T generated with CRISPR from Caribou Biosciences is currently in a Phase I clinical trial for the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma (NCT04637763) [99, 100].
Lentiviral transduction and TALENs have been combined to develop a therapy for pediatric refractory relapsed B-cell acute lymphoblastic leukemia. The lentivirus was used to introduce the CAR, and TALENs were used to edit the native TCR and CD52 gene loci to generate an allogeneic product that achieved remission ahead of stem cell transplantation in 2 infants [101].
Treatment of solid tumors remains a key challenge for CAR-T therapies. Variations in CAR therapies, including CAR natural killer cells and CAR macro­phages, are under current clinical evaluation in solid tumor indications. Genetic engineering presents a potential solution regarding solid tumors. Genetic engineer­ing may allow for the ne-tuning of cells to overcome the hypoxic and immunosup­pressive microenvironment of solid tumors [53].
9 CAR-T Bioprocessing
Table 9.5 Strategies for optimizing production workows and quality attributes that may be affected
Production workow Strategies
Apheresis collection Collecting apheresis before treatment
with frontline chemotherapy or radiation regimens
Cell selection and expansion
Vector preparation and transduction
Formulation Selection of formulation buffers to
Infusion Cold chain temperature excursions
Dry thaw cryopreserved apheresis Reduction in human-derived media components Implement end-to-end, closed systems from cell selection to nal formulation
Media optimization Closed automated systems Quality control assays Plasmid design Filtration and purication
increase T-cell stemness Optimization of the cryopreservant type and concentration Container closure system integrity Container lling approaches (automated versus manual)
Thawing rate and type Hold time and infusion rate (in-use stability)
Quality attributes potentially affected
Purity, viability
Purity, sterility, viability
Viability Sterility, viability, potency Potency, efcacy High titer, transduction efciency High recovery, stability, potency,
Potency, cell count, transduction efciency Cell count, viability, potency Cell count, viability, sterility Cell count, viability, potency, transduction efciency, sterility
Viability, potency, transduction efciency Cell count, viability, potency Viability, potency, cell count (dose level)
251
The model of manufacturing for CAR-T therapies requires different demands than a traditional biopharmaceutical therapy. Because CAR-T manufacturing begins after a patient has fallen ill, the time from apheresis to drug product administration (“vein to vein” time) is critical to patient success. To this end, decentralized manu­facturing may present a manufacturing model that is more benecial to patients than centralized manufacturing. In decentralized manufacturing, a central hub can man­age multiple, smaller manufacturing facilities located closer to the patient and reduce the footprint of a complicated supply chain associated with centralized man­ufacturing [97]. Manufacturing at the point of care is another model for consider­ation. A collaboration between Lonza and CellPoint is exploring point of care manufacturing with Lonza’s Cocoon system for cell expansion, reducing vein to vein time to 5–7days [102]. As the eld continues to grow, decentralized manufac­turing may be key to expanding access to patients in new geographical areas and delivering medicines as quickly as possible.
As the CAR-T and immunotherapy eld continues to make exciting strides and new clinical offerings, manufacturing advancements are also growing to meet
252
A. Adeniran et al.
demands for scalability, price, and patient access. In this chapter, we have discussed current manufacturing processes for CAR-T therapies and key challenges and con­cerns for this growing eld. CAR-T cells hold great promise as a curative therapy, and as the knowledge of the therapy and eld grows, research scientists, manufac­turers, and clinical partners can continue to push the bounds of immunotherapy to offer more options for patients.
Acknowledgments The authors thank Dr. Alexandra McGregor for helpful discussions around potency assays.

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Chapter 10
CRISPR Technology andIts Application inTherapeutics
RigelKishton, MontseMorell, KevinHolden, MeenakshiPrabhune, RebeccaRoberts, BobbyMoon, andRebeccaL.Nugent
Abstract Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)
technology is one of the most signicant scientic breakthroughs of this century, revolutionizing therapeutics. A component of bacterial immune systems, CRISPR has been repurposed to precisely edit DNA sequences. The accuracy, efciency, and simplicity of CRISPR technology have provided exciting new avenues to modify DNA and RNA for the treatment of human diseases. This includes both gene ther­apy, in which genes are edited invivo in patients, and gene-edited cell therapy, in which cells are edited exvivo and transfused into patients. This chapter is a compre­hensive guide to CRISPR gene editing and its applications in biotherapeutics. It begins with an introduction to CRISPR-Cas9 technology, examining its discovery and adaptation, mode of action, advantages over previous tools, derivatives of the original CRISPR-Cas9 technology, and gene editing methods. This is followed by a review of the applications of CRISPR technology in biotherapeutics, including both gene therapies and gene-edited cell therapies for the treatment of three disease cat­egories: genetic disorders, infectious diseases, and cancer. Relevant preclinical research and/or clinical trials are discussed for each disease category. The nal
R. Kishton Moonwalk Biosciences, South San Francisco, CA, USA e-mail: rigel.kishton@moonwalk.bio
M. Morell EditCo Bio, Redwood City, CA, USA e-mail: montse.morell@editco.bio
K. Holden · R. Roberts · B. Moon Synthego Corporation, Redwood City, CA, USA
M. Prabhune The Scientist, Lab X Media Group, Midland , ON, Canada e-mail: mprabhune@the-scientist.com
R. L. Nugent (*) Tessera Therapeutics, Sommerville, MA, USA e-mail: rnugent@tesseratx.com
K. Gadamasetti, S. A. Kolodziej (eds.), Bioprocessing, Bioengineering and Process Chemistry in the Biopharmaceutical Industry,
https://doi.org/10.1007/978-3-031-62007-2_10
259© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
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