May 28, 2005 Natural killer (NK) immune system cells can be genetically modified to brandish a powerful "on-switch" that prompts them to aggressively attack and kill leukemic cells. This finding, from researchers at St. Jude Children's Research Hospital, suggests a way to improve the outcome of children who receive treatment for acute lymphoblastic leukemia (ALL) or other blood cancers.
Results of the St. Jude study are published in the current online issue of Blood.
The researchers demonstrated how to overcome significant technical hurdles that have until now slowed development of NK-based therapies for ALL, according to Dario Campana, M.D., Ph.D., a member of St. Jude Hematology-Oncology and Pathology, and senior author of the Blood report. Progress in adapting NK cells to the treatment of ALL had been significantly hampered because researchers were not able to grow large numbers of these immune cells in the laboratory, and because NK cells normally have only weak anti-leukemic activity.
The key breakthroughs made by the St. Jude team were the development of a laboratory technique for rapidly producing a large, pure population of NK cells from a small sample of blood; and developing a technique for genetically modifying NK cells so that they would become potent killers when they encountered leukemic cells.
In order to grow large populations of NK cells, the team started with samples of blood containing a variety of different immune system cells. They placed this sample into a dish containing a type of human leukemia cell called K562. Campana's team genetically modified the K562 cells so they carried on their surfaces many copies of two different proteins, 4-1BBL and IL-15. The genetically modified K562 cells quickly stimulated the expansion of the NK cell population to more than10,000 times their original number. The technique triggered growth of NK cells specifically, which greatly simplified the ability of the researchers to collect a pure population of these immune cells.
The researchers then genetically modified the growing NK cells so they carried on their surface an artificial receptor that made them particularly aggressive and effective killers that attacked only leukemic cells. A receptor is a protein that binds to a specific target molecule. The artificial receptor on the NK molecule was designed to recognize a protein called CD19, which is found on the surface of leukemic cells. When the receptor bound to CD19 on leukemic cells, it set off a reaction that super-charged the killing activity of the NK cell.
"By developing a technique for cultivating large numbers of NK cells from a small blood sample, we made it practical to consider them a potential treatment against many different types of cancer," Campana said. "By genetically modifying NK cells so they expressed the CD19 receptor, we made them specifically effective against ALL cells."
A potential clinical application for the technology developed in this study is in leukemia patients who are treated with hematopoietic (blood cell-forming) cell transplantation. In this case, NK cells will be derived from the transplant donor, expanded and genetically modified. These modified NK cells will then be infused into the patient after the transplant in order to eliminate residual leukemic cells. In another application, NK cells could be obtained from a patient while in remission and then reinfused after genetic modification if the patient suffers a resurgence of the leukemia.
"We look forward to seeing this strategy being added to the management of children with ALL," said Chihaya Imai, M.D., the postdoctoral student who did most of the work on this project.
The other author of this study is Shotaro Iwamoto, M.D., of St. Jude.
This work was supported in part by the National Cancer Institute and ALSAC.
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