Reprogramming T Cells Without Using Viral Vectors
Researchers utilized 2 proof-of-principle models to test the ability of the engineered T cells to repair inherited mutations.
Nonviral Approaches: More Commercially Feasible?
Though the team determined that the knock-in efficiency was lower with nonviral targeting than with AAV vector templates of comparable size, the T cells could be expanded rapidly over the course of 10 days, and the T cells best suited to attack cancerous lesions could be sorted out and cultivated. In all, the researchers concluded their method of T-cell engineering could be used to make a novel construct in about a week, suggesting it could be a strong competitor to other cell therapy manufacturing methods.
Marcela Maus, MD, PhD, director of the cellular immunotherapy program at Massachusetts General Hospital (who is not involved in the study), called the paper "exciting." She agreed that modified viruses are expensive to make in the clinical setting, and there are long wait lists to make these vectors. She confirmed the research "demonstrates that T cells can be genetically modified efficiently using a combination of CRISPR-Cas9 technology and electroporation, and that these work as well as vector-modified T cells in test tubes and in a mouse model." She added, "This new technique offers the possibility of making new types of engineered T cell therapies much faster and cheaper than our current technologies."
The news comes at a time when manufacturers are frantically preparing to ramp up adeno-associated viral (AAV)-based production to meet the demands of new types of therapies in the pipeline that rely on these delivery vehicles, particularly, cell and gene therapies.2
The cost of producing the quantity of vectors thought to be necessary to deliver enough genetic material into cells is expected to be extraordinary. In addition, though site expansions at contract development and manufacturing organizations are occurring, many of these companies providing viral vectors to drug makers are at capacity or close to it.
Though there were many collaborators on the Nature study, a company that stuck out was Takara Bio, which is developing drugs for the treatment of malignant melanoma, pancreatic cancer, synovial sarcoma, and adult acute lymphocytic leukemia. In addition, the study's lead author, Alexander Marson, assistant professor at UCSF, is a cofounder of Spotlight Therapeutics and an advisor to PACT Pharma and Juno Therapeutics (a company also developing immunotherapies).
- Roth TL, Puig-Saus C, Yu R et al. Reprogramming human T cell function and specificity with non-viral genome targeting. Nature. doi: 10.1038/s41586-018-0326-5
- Plieth J. Vantage point – The $100,000 problem gene therapy companies would rather not mention. EP Vantage website. http://www.epvantage.com/Universal/View.aspx?type=Story&id=798570&isEPVantage=yes. Published June 25, 2018. Accessed July 11, 2018.