Human Pluripotent Stem Cells as a Renewable Source of Natural Killer Cells

Human pluripotent stems cells provide an ideal source for the study of hematopoietic differentiation. Natural killer (NK) cells are lymphocytes that play a key role in innate immunity against viral infections as well as malignancies. The development and differentiation of NK cells have been an area of increasing research interest due to their clinical utility in treating multiple types of cancer and potentially infectious disease. Our initial studies to derive NK cells from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) used a stromal cell co-culture method with relatively poor-defined conditions. Subsequent studies have utilized a stroma-free embryoid body (EB) method to generate hemato-endothelial precursor cells followed by in vitro NK cell differentiation in defined conditions. Further expansion of these hESC- and iPSC-derived NK cells can be done through the use of interleukin (IL)-21 expressing artificial antigen-presenting cells (aAPCs). Combining these methods, we can efficiently generate enough NK cells required for clinical therapies from a small number of undifferentiated human pluripotent stem cells. These methods enable hESCs and iPSCs to be used to produce an essentially unlimited amount of homogenous NK cells that can be used as a standardized, off-the-shelf immunotherapy for the treatment of refractory cancers and other diseases.