Selectively Enhanced NK-92 cells: a Safer Form of Cellular Immunotherapy

NK-92 is an investigational, cellular immunotherapy for the treatment of various malignancies. A highly-functional, human cancer cell line resembling natural killer cells, it is an off-the-shelf therapy, and holds the potential to be more widely available than current cell-based immunotherapies. Phase I clinical trials have demonstrated a favorable safety profile, and several phase II trials are already underway.

As a cancer cell line, NK-92 cells can be genetically engineered for enhanced function. Current modifications include addition of an activating receptor and removal of susceptibility to negative regulation. These changes focus on different aspects of NK-92 activity, but lead to the same endpoint – a quantitative increase in NK-92 activation. While this increases drug potency, it also augments off-target effects, and therefore toxicity. In fact, the same is true of all current immunotherapies, which non-selectively increase activation levels. We decided to take a different approach.

IFNG-AS1 is a long, non-coding RNA which is a positive regulator of interferon gamma (IFNγ) secretion. We found that IFNG-AS1 is functional in human natural killer cells, and, as in T cells, is induced upon cellular activation. When we overexpressed IFNG-AS1 in NK-92 cells, we found a curious phenomenon – increased IFNγ secretion upon cellular activation, but no increase in spontaneous secretion. This allows for a more potent response, as with the other transfectants, but avoids the hazards of increased side effects. We therefore termed the cells "selectively enhanced" or seNKs, a new concept in the field of immunotherapy.