Might CAR-NK–Based Immunotherapy Be More Effective, Less Toxic?

A team of investigators from the University of California San Diego School of Medicine and the University of Minnesota has concluded, based on a murine study, that it may be possible to engineer natural killer (NK) cells to include chimeric antigen receptors (CARs) and thereby create a less toxic form of CAR immunotherapy. The study was published online in Cell Stem Cell. It showed that similarly modified NK cells derived from human induced pluripotent stem cells (iPSCs) displayed heightened activity against a mouse model of ovarian cancer.

The findings suggest a major advantage over current CAR T-cell–based immunotherapies because NK cells can be safely delivered in an off-the-shelf manner without patient matching. Senior author Dan Kaufman, MD, PhD, who is a professor of medicine in the Division of Regenerative Medicine and director of cell therapy at UC San Diego School of Medicine, San Diego, Calif., said one of the main challenges of immunotherapy has been the clinical manufacture of modified cells.

CAR-T cell–based immunotherapies have garnered considerable attention and investment in recent years. T cells are extracted from a patient’s blood, genetically modified with a chimeric antigen receptor, and then grown in large numbers in a laboratory.   

Kaufman said one batch of iPSC-derived NK cells potentially can be used to treat thousands of patients. This would enable standardized off-the-shelf treatments that could be used in combination with other anticancer therapies. He and his colleagues have shown that it is possible to engineer iPSCs and create chimeric antigen receptor–expressing NK cells to better target refractory cancers that have resisted other treatments.

Kaufman noted that CAR T-cell immunotherapies have been associated with severe toxicities, including unexpected organ damage and death. Previous research that he and others have conducted suggests that NK cells do not trigger similar toxicities, and the latest study reported few adverse effects in mouse models.

In their research, the team tested CAR-NK cells derived from human iPSCs in an ovarian cancer xenograft mouse model. They compared the antitumor activity against other versions of NK cells and CAR T cells. The NK cells demonstrated activity to that of CAR T cells, but with significantly less toxicity. Kaufman said the data indicate that ovarian cancer may be a good first target, but added that other solid tumors (such as breast cancer, brain tumors, and colon cancers) as well as blood cell cancers (such as leukemias) are also likely to be suitable targets of iPSC-derived NK cells.

Renier J. Brentjens, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, said it is common for toxicities to occur in humans even though they were not evident in the animal studies. “Hypothetically, any type of these (approaches) shows promise and should be moved forward to the clinical study. The promise is high. It might work, but whether it is safer or better than CAR T cells will have to be determined with clinical trials,” Dr. Brentjens said in an interview with Cancer Network.

Brentjens added that the fact that this could be an off-the-shelf product makes it very attractive in terms of costs and convenience. “With any kind of approach where you can potentially make a one-size-fits-all product that is equally effective or better, you will have an advantage over the current system, which is cumbersome and expensive,” Brentjens said.