CAREER: Novel expansion strategies for biomanufacturing of natural killer cells

Engineered T cell therapies were recently approved by the Food and Drug Administration to fight cancer. These therapies harness the body's immune system to more effectively attack advanced stage cancer. Natural killer (NK) cells are a promising immune cell population for the treatment of blood cancers and solid tumors. Safe, large-scale NK cell production is needed to effectively treat large numbers of patients. Immune cells are complex, so producing NK cells in large quantities is difficult. Guaranteeing that each cell has a high level of activity adds a level of complexity to therapeutic cell manufacturing. One challenge is to develop a process that does not require the introduction of other cells to activate the NK cells. The investigators propose to develop an artificial lipid vesicle that will activate the NK cells. This approach will be useful in the production of a variety of therapeutic cells. Education and outreach activities are also planned. Women and underrepresented minorities will be actively recruited to pursue STEM careers. This will be supported by videos and other curricular material developed to bolster competency in mathematics.

Large-scale growth of NK cells currently requires multiple rounds of stimulation with artificial antigen-presenting cells (aAPCs). These are most often derived from the K562 leukemia cell line. The use of these feeder cells leads to regulatory concerns in clinical biomanufacturing processes and hinders therapeutic adoption. This project will develop feeder-free approaches for large-scale NK cell expansion. By elucidating the mechanisms through which co-culture with aAPCs stimulates NK cells, processes for expansion of NK cells without cellular aAPCs can be developed. NK metabolism will be characterized during multiple rounds of stimulation. Understanding how aAPC stimulation induces NK growth is of particular interest. RNA-seq analysis will be performed before and after each round of stimulation to identify pathways that are modulated. These results will inform the design of synthetic phospholipid vesicles that present critical activating signals to the NK cells.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.