ddn Cancer Research News Exclusive: Natural-born killers

International research team discovers new method for mass- production of natural cancer-killing cells

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DURHAM, N.C.—A team of scientists from the University ofMinnesota, the Integrated Center of Cellular Therapy and Regenerative Medicineof St. Anne's University Hospital Brno (Czech Republic) and the University ofTexas, Houston, have published a new study on a method for mass-producing NKcells in the lab in quantities that could take NK cells-based therapies out ofthe lab and into the clinic.
Labs have been producing NK cells from human embryonic stemcells and induced pluripotent stem cells for some time, but up until this pointit has only been possible on a small scale. This new method ramps up the outputwhile streamlining the process to require less time and work.
"Human NK cells have been used to treat patients withrefractory malignancies, but a major hindrance to expanded use has been theinefficiency of production," Anthony Atala, M.D., editor of STEM CELLSTranslational Medicine and director of theWake Forest Institute for Regenerative Medicine, said in a press release. "Thecurrent study has identified a two-stage culture system to efficiently producethe cells in a manner more suitable to clinical translation than previousmethods."
NK cells are a type of white blood cell known aslymphocytes. In a 2008 article that appeared in Nature Immunology ("Functions of natural killer cells), NK cells aredescribed as "effector lymphocytes of the innate immune system that controlseveral types of tumors and microbial infections by limiting their spread andsubsequent tissue damage. Recent research highlights the fact that NK cells arealso regulatory cells engaged in reciprocal interactions with dendritic cells,macrophages, T cells and endothelial cells. NK cells can thus limit orexacerbate immune responses. Although NK cells might appear to be redundant inseveral conditions of immune challenge in humans, NK cell manipulation seems tohold promise in efforts to improve hematopoietic and solid organtransplantation, promote antitumor immunotherapy and control inflammatory andautoimmune disorders."
Dan Kaufman, M.D., Ph.D., of the Stem Cell Institute of theUniversity of Minnesota, notes that NK cells comprise roughly "10 percent ofthe lymphocytes in your blood," and demonstrate both antiviral and antitumoractivity. Kaufman was the lead investigator for the study.
The study covers a "revamp" of their previous approach inproducing these cells in greater quantities, Kaufman says. The original study,"Human embryonic stem cell-derived NK cells acquire functional receptors andcytolytic activity," appeared in the Journal of Immunology in 2005. In this latest study, "Clinical-scalederivation of natural killer cells from human pluripotent stem cells for cancertherapy," Kaufman says they got rid of xenogeneic and stromal cell lines, whichare typically mouse lines, and are now able to mass-produce these cells"without any foreign cells or foreign serum," which allows them to generatethese cells in "completely defined conditions that eliminate some of thepossible barriers to clinical use because of FDA issues." The team was alsoable to adjust their culture processes to scale up the number of cells to reachlevels sufficient for treating patients.
"Part of this is based just on the change of cultureconditions we did, and then part was too the collaboration with the group at MDAnderson who provided what are called artificial antigen-presenting cells, andthese were shown to give several lots more expansion of these NK cells that wecan then use," Kaufman explains.
NK cells seem to be most effective when targeting leukemiasor "liquid tumors," which Kaufman posits may be due to certain receptors thatmake the tumors more susceptible to NK cells. Other tests have been done withmelanoma and some types of kidney cancers, which he notes "tend to be moreimmune-susceptible." Moving forward, he says, the team will be trying to useembryonic stem cells and induced pluripotent stem cells to determine whetherit's possible to enhance the receptors and other facets that would lead toincreased termination of tumors that generally present with less sensitivity.
Kaufman says they are reaching out tovarious outfits to see if they can find support for scaling this approach upand "either through academic or commercialization, provide a product that wecould put into clinical trials." The NK cells have been shown in other studiesto "have activity against things like pancreatic cancer, lung cancer, coloncancer, breast cancer," he adds.
Should they find that support, he says the most likely formthat this approach will take will be to pair the NK cells with nanoparticles todeliver them to the tumors, or to engineer the NK cells with specificreceptors.
"We think that this type of approach combined withchemotherapy—the chemotherapy might kill off most of the tumor, but the NKcells, the targeted NK cells, would then be able to kill off and mop up anyresidual tumor cells," Kaufman explains.
The most recent study appeared in STEM CELLSTranslational Medicine March 20.

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