Selecting a Cell Engineering Methodology During Cell Therapy Product Development

Abstract

When considering the development pathway for a genetically modified cell therapy product, it is critically important that the product is engineered consistent with its intended human use. For scientists looking to develop and commercialize a new technology, the decision to select a genetic modification method depends on several practical considerations. Whichever path is chosen, the developer must understand the key risks and potential mitigations of the cell engineering approach. The developer should also understand the clinical implications: permanent/memory establishment versus transient expression, and clinical manufacturing considerations when dealing with transplantation of genetically engineered cells. This review covers important topics for mapping out a strategy for developers of new cell-based therapeutics. Biological, technological, manufacturing, and clinical considerations are all presented to map out development lanes for the initiation and risk management of new gene-based cell therapeutic products for human use.

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

“…Developers should carefully consider the implications of the chosen engineering method during early product development phases, as it must comply with pharmaceutical and commercial requirements and therefore could increase the complexity of the development process. For γ-retroviral and lentiviral systems, the costs of producing large quantities of GMP-grade virus remain high and often require outsourcing to third-party contract development and manufacturing organizations (CDMOs) [ 262 ].…”

“…The risk-based approach should also be applied to the design of the manufacturing process, to assess critical attributes and parameters and to increase the assurance of producing batches of the intended quality. The risk of cross-contamination can be minimized by handling one viral vector in one clean room suite at a given time; if the same facility is shared between products manufactured with different vectors, their production could be staggered to avoid simultaneous manipulation [ 262 ]. As this can impact timelines for product availability and clinical testing, careful planning is required.…”

Peptide-mediated delivery of CRISPR enzymes for the efficient editing of primary human lymphocytes

“…PERC minimizes cell handling steps (as compared with electroporation) and could be incorporated into fully automated cell processing pipelines. Although middle-income regions may have access to therapeutic cell manufacturing hardware compatible with viral transduction, there is a critical lack of infrastructure such as clean rooms mandated by electroporation-based editing protocols 42 . PERC minimizes cell handling steps, is compatible with broadly available automated cell manufacturing hardware and could be incorporated into point-of-care manufacturing, thus enabling clinical applications that otherwise would be impractical.…”

Genetic Modification as a New Approach to Ameliorate the Therapeutic Efficacy of Stem Cells in Diabetic Retinopathy

“…92 Generally AAV is regarded to be safer than lentiviral because lower chances for host genome integration, but more knowledge is required to completely comprehend the risk of using AAV as it is still possible for genome integration to occur. 93 With non-viral vectors like electroporation and liposomes, risk for immunogenicity or for the genome to integrate into the host is less than viral vectors. 23 Nevertheless, there are other drawbacks besides low efficiency that limit its uses.…”