As the seven FDA approved CAR T cell products continue to prove therapeutically and commercially viable, the development and scalability of CAR manufacturing platforms within academic cell production facilities will be critical to keeping pace with industry partners and ensuring academic workflows can be transferred to commercial production. CAR manufacturing must be further streamlined, standardized, and economized. To this end, closed and automated manufacturing systems offer a means of reducing labor costs, alleviating GMP manufacturing environmental requirements, and minimizing the risk associated with contamination or product variability. The CliniMACs Prodigy, a combination of a cell washer, magnetic cell separation system, and cell cultivation device is likely the most feasible means of achieving this goal, as it is one of the systems available that can enrich cell products within a closed environment (53). The Prodigy has already demonstrated the ability to select and expand T cells from preselected populations or whole apheresis, enabling the scalable production of CAR T cells in a controlled, GMP-compliant manner with no advanced manufacturing training necessary (8183). Closed-system continuous perfusion bioreactors offer varying degrees of automatic T-cell selection, expansion, vector transfection or transduction, cell washing, concentration, harvesting, cell product formulation, and in-process control testing. A number of manufacturing studies conducted at academic institutions have demonstrated that closed-system bioreactors, including the Prodigy, limit microbial contamination and are capable of generating CAR T cells with tumor-specificity, functionality, and phenotypic expression similar to immunotherapies generated by other methods (28, 8486). Although cell products did meet release criteria for expansion, cytotoxicity, and sterility, issues did arise with variability in cell growth, vector copy number, and myc overexpression (86). Transduction efficiency and cell yield are sufficient for clinical application in the manufacturing of CAR T-cell and DC therapies (85, 87, 88). Importantly, the use of an automated, closed-loop manufacturing system has already proven successful in the treatment of relapsed and refractory B-cell malignancies in trials conducted at academic medical centers (82, 89).

Refining transduction techniques beyond -retroviral and lentiviral vectors will also give academic manufacturing programs more flexibility in developing future CAR T-cell therapies. The use of SB, CRISPR Cas9, and mRNA gene transfer systems would circumvent the need for costly release testing and viral vector production. Concerns related to transduction efficacy, cell viability, duration of culture, and the duration of expression in the case of mRNA can only be dispelled through expanded clinical trials. Likewise, production variability in relation to treatment outcomes must be closely monitored before these modalities can be more widely adopted in academic manufacturing protocols.

The CAR transgene itself can also be updated through continued exploration of costimulatory molecules, suicide genes, and expanded CAR T-cell targets. CD20, CD22, CD30, CD33, CD138, CD171, CEA, EGFR, EFGRvIII, ErbB, FAP, GD2, Glypican 3, Her 2, Mesothelin, and NKG2D are all tumor associated proteins currently being targeted by academic programs designing CAR T cells (90). Targeting novel surface receptors is proving to be a key component of successful CAR T-cell products for the treatment of solid neoplasms. Tumor heterogeneity and antigen loss as a means of therapeutic escape reinforce that creating CAR T-cell therapies that target multiple surface markers through a pooled product may further improve clinical responses and prevent disease relapse.

Given the commercial success of multiple CAR T-cell products, collaboration with industry partners will further improve these manufacturing tools. When leveraged with the resources and finances available to the biopharma industry, the extensive experience academic programs have in the CAR T-cell arena can facilitate needed technological advancement, accelerate workflow development, and promote the expansion of CAR T-cell therapies to a greater patient population. The T-Charge platform, developed by Novartis, could be a particularly apt example of the benefit collaboration could pose for academic manufacturing centers; although only abstract data are currently available, the platform has demonstrated the ability to retain T-cell stemness and rapidly produce CAR T-cell products in less than 2 days.

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