Genetic Modification of Natural Killer Cells for Leukemia Therapies

Natural killer (NK) cells have the capacity to recognize and kill a wide range of cancer cells. However, many cancer cells are resistant to NK cell cytotoxicity, mainly because they express molecules which inhibit NK cell activation. Previous studies have shown that enforced expression of chimeric receptors composed of single-chain variable domain of murine antibodies and human signaling molecules can redirect the specificity of T lymphocytes. The success of this approach depends on the identification of a suitable target molecule on cancer cells and on the ability of the receptor to deliver appropriate activation signals. We developed a method to express chimeric receptors in NK cells. Considerable NK cell expansion was obtained by co-culturing peripheral blood cells with the leukemia cell line K562 modified to express membrane bound-interleukin 15 and the ligand for the costimulatory molecule 4-1BB. Expanded NK cells were then transduced with anti-CD19 receptors which deliver activation signals through CD3ζ and 4-1BB. NK cells expressing these receptors became highly cytotoxic against NK-resistant CD19+ leukemic cells. We here review the methodologies for expanding and redirecting the specificity of NK cells, explain the rationale for NK-cell therapies of leukemia and lymphoma, describe potential targets for genetically-modified NK cells, and discuss future clinical applications of NK cell expansion and genetic modification in cancer therapy.