NK cells grown from stem cells have shown promising potential in the fight against leukemia.

Researchers from the United States using induced pluripotent stem cells (iPSCs) and removal of a key gene created natural killer cells that have increased activity in the fight against leukemia, both in vivo and in vitro.

Natural killer (NK) cells are lymphocytes of the same family with T and B cells that are involved in the functioning of innate immunity. They circulate throughout the body and are among the first to respond to the presence of foreign cells or invaders, especially viruses and early signs of cancer.

NK cells are very promising as the basis for antitumor therapy capable of detecting malignant cells, but their effectiveness is limited.

In a new study, a group led by senior author Dan Kaufman, MD, PhD, professor of medicine in the Division of Regenerative Medicine, director of cell therapy at University of California (UC) San Diego School of Medicine and a faculty member of both the Sanford Consortium for Regenerative Medicine and the Sanford Stem Cell Clinical Center at UC San Diego Health, expanded the potential of natural killers in two ways.

First, the researchers created NK cells from iPSCs, which are derived from skin or blood cells that have been reprogrammed back to an embryonic pluripotent state. This strategy allows a standardized population of cells to be produced and eliminates the need for individual cells for each patient.

Second, the researchers deleted a gene called CISH in NK cells created from iPSCs. The CISH gene regulates the expression of a protein that suppresses cytokine signaling. Cytokines are molecules that inform the cells of the immune system (macrophages, lymphocytes, fibroblasts) about the location of infection, inflammation and trauma.

«Deletion of CISH in NK cells removes an internal «checkpoint» that is normally activated or expressed when NK cells are stimulated by cytokines, such as IL15», – said Kaufman. «We found that CISH-deleted iPSC-derived NK cells were able to effectively cure mice that harbor human leukemia cells, whereas mice treated with the unmodified NK cells died from the leukemia».

These studies demonstrate that we can now edit iPSC-derived NK cells to remove an inhibitory gene inside the cell to improve activation of NK cells. We demonstrate that the CISH deletion improves NK cell function in at least two different ways.

First, it removes a brake on IL15 signaling, with improves NK cell activation and function, even at low IL15 concentrations. Second, it leads to metabolic reprogramming of the NK cells. They become more efficient at energy utilization, which improves their function in vivo».

Kaufman said that he and his colleagues are now working to convert the results into clinical therapy. Their study was published in the online issue of Cell Stem Cell magazine on June 11, 2020.

«As iPSC-derived NK cells are now in clinical trials to treat both hematologic (blood) malignancies and solid tumors, we expect that CISH-deleted iPSC-NK cells can provide an even more effective treatment.

Importantly, iPSCs provide a stable platform for gene modification and since NK cells can be used as allogeneic cells that do not need to be matched to individual patients, we can create a line of appropriately modified iPSC-derived NK cells suitable for treating hundreds or thousands of patients as a standardized, «off-the-shelf» therapy», – said Kaufman.