Engineered to hit CD19, boosted to persist, natural killer cells now in first–in–human clinical trial.
Immune cells with a general knack for recognizing and killing many types of infected or abnormal cells also can be engineered to hunt down cells with specific targets on them to treat cancer, researchers at The University of Texas MD Anderson Cancer Center reported in the journal Leukemia.

The team’s preclinical research shows that natural killer cells derived from donated umbilical cords can be modified to seek and destroy some types of leukemia and lymphoma. Genetic engineering also boosts their persistence and embeds a suicide gene that allows the modified cells to be shut down if they cause a severe inflammatory response.

A first–in–human phase I/II clinical trial of these cord–blood–derived, chimeric antigen receptor–equipped natural killer cells opened at MD Anderson in June for patients with relapsed or resistant chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), or non–Hodgkin lymphoma. All are cancers of the B cells, another white blood cell involved in immune response.

“Natural killer cells are the immune system’s most potent killers, but they are short–lived and cancers manage to evade a patient’s own NK cells to progress,” said Katy Rezvani, MD, PhD, professor of Stem Cell Transplantation and Cellular Therapy.

“Our cord–blood derived NK cells, genetically equipped with a receptor that focuses them on B–cell malignancies and with interleukin–15 to help them persist longer – potentially for months instead of two or three weeks – are designed to address these challenges,” Rezvani said.

The clinical trial is funded by MD Anderson’s Moon Shots Program™, designed to more rapidly develop life–saving advances based on scientific discoveries.

The chimeric antigen receptor (CAR), so–called because it’s added to the cells, targets CD19, a surface protein found on B cells.

In cell lines and mouse models of lymphoma and CLL, CD19–targeted NK cells killed cancer cells and extended survival of animals compared to simply giving NK cells alone. Addition of IL–15 to the CD19 receptor was crucial for the longer persistence and enhanced activity of the NK cells against tumor cells.

NK cells are a different breed of killer from their more famous immune system cousins, the T cells. Both are white blood cells, but T cells are highly specialized hunters that look for invaders or abnormal cells that bear a specific antigen target, kill them and then remember the antigen target forever.

Natural killers have an array of inhibitory and activating receptors that work together to allow them to detect a wider variety of infected, stressed or abnormal cells.

“By adding the CD19 CAR, we’re also turning them into guided missiles,” said Elizabeth Shpall, MD, professor of Stem Cell Transplantation and Cell Therapy.

Using a viral vector, the researchers transduce NK cells taken from cord blood with the CD19 CAR, the IL–15 gene, and an inducible caspase–9–based suicide gene.

Cell line tests found the engineered NK cells to be more efficient killers of lymphoma and CLL cells, compared to unmodified NK cells, indicating the engineered cells’ killing was not related to non–specific natural killer cell cytotoxicity.

Another experiment showed the engineered cord blood NK cells killed CLL cells much more efficiently than NK cells taken from CLL patients and engineered, highlighting the need to transplant CAR–engineered NK cells from healthy cord blood rather than use a patient’s own cells.