Researchers have changed leukemia cells into natural killer cells by adding a specific antibody to bone marrow cells from patients with acute myeloblastic leukemia. The induced natural killer cells killed leukemia cells in culture. The antibody does not trigger the same conversion in bone marrow from healthy patients.
An antibody can force leukemia cells to convert into natural killer (NK) cells that attack other cancer cells, researchers have found. Treating patients with the antibody might cause cancer cells to turn against and destroy their brethren.
By screening antibody libraries, Richard Lerner, MD, a professor of immunochemistry at the Scripps Research Institute in La Jolla, CA, and colleagues have identified large numbers of antibodies that bind to receptors on cells and control their differentiation. Most of these molecules stimulate cells to continue along the same developmental path, but a few cause cells to switch lineages, such as pushing the normal precursors of granulocytes to differentiate into nerve cells.
In a new study, Lerner's team asked whether some of their antibodies could spur cancer cells to revert to benign cells. To test that possibility, they obtained bone marrow or blood samples from seven patients with acute myeloblastic leukemia. This cancer results from the accumulation of myeloblasts, immature hematopoietic cells that normally give rise to basophils, neutrophils, dendritic cells, and other cell types.
The researchers started by adding 20 differentiation-promoting antibodies to cultures of bone marrow from the patient whose myeloblasts were the most stem cell–like. The antibody with the biggest impact stimulated the thrombopoietin receptor (TPOR), which normally drives the maturation of platelets. As the researchers reported in Proceedings of the National Academy of Sciences, this antibody caused about 80% of the patient's myeloblasts to differentiate, and it had the same effect in samples from five of the other patients.
Some of the differentiated cells induced by the TPOR agonist antibody resembled dendritic cells, but some of them resembled NK cells, which can attack and destroy cancer cells. They sent out sharp projections that bored into neighboring cells, and they produced some of NK cells' chemical weapons—perforin, IFNγ, and granzyme B. In bone marrow from healthy patients, the antibody stimulated formation of megakaryocytes, the cells that produce platelets, but not dendritic cells or NK cells, suggesting that it won't trigger abnormal differentiation of healthy cells.
The researchers wondered whether the NK cells induced by the antibody could perform that function. They anchored the converted NK cells in culture dishes and then added leukemia cells. After 24 hours, 13% to 16% of the leukemia cells were dead, suggesting that the NK cells were living up to their name. To determine whether the same NK cells might attack other cancers, they added breast cancer cells to NK cells. This time, however, the cancer cells survived. As Lerner puts it, the NK cells are “fratricidal,” destroying only the cancer cells from which they descended.
“This opens a way to select antibodies that will differentiate cancer cells into a less malignant phenotype,” Lerner says. “The fact that they kill is a bonus.”
“The general observation that you can make cancer cells turn into cancer-killing cells—if true, that would be really remarkable,” says Lewis Lanier, PhD, of the University of California, San Francisco, who wasn't connected to the study. However, he cautions, the researchers also need to show that the cells revert from cancer cells into normal cells.
Lerner says that he and his team plan to further test the antibody, which they have named Fratricidin, in tissue culture and then in animals.
- ©2015 American Association for Cancer Research.