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After decades since the discovery of natural killer (NK) cells as potential effector cells fighting malignantly transformed and virally infected cells, little progress has been made in their clinical application. This yet unrealized therapeutic effect is presumably, at least in part, due to low numbers of functional NK cells that could be obtained from the peripheral blood relative to tumor burden. Our group hypothesized that a relatively small NK cell number to targeted malignant cells is the cause of a lack of clinical effect. We pursued obtaining large numbers of NK cells via ex vivo expansion using feeder cells that express membrane-bound IL-21. Early clinical studies demonstrate safety of administration of ex vivo expanded NK cells after transplantation using this method and suggest a therapeutic benefit in terms on decreasing relapse rate and possible control of viral infections post-transplant can be achieved. Successful application of NK cells after hematopoietic stem cell transplantation opens the possibility to effectively enhance the anti-tumor effect and decrease relapse rate post-transplant. Moreover, high doses of NK cells could prove more efficacious in enhancing anti-tumor effects, not only in hematological malignancies, with our without transplantation, but also in solid tumor oncology. [ABSTRACT FROM AUTHOR]