Findings from the new study—published recently in Cell Stem Cell, in an article entitled “Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-Tumor Activity”—are significant because NK cells may offer distinct advantages over T cells, including the ability to safely deliver engineered NK cells in an off-the-shelf manner without patient matching.
“One of the main challenges of immunotherapy has been the clinical manufacture of modified cells,” explained senior study investigator Dan Kaufman, M.D., Ph.D., professor of medicine in the division of regenerative medicine and director of cell therapy at UC San Diego School of Medicine. “We’ve shown that you can engineer iPSCs, and create chimeric antigen receptor–expressing NK cells to better target refractory cancers that have resisted other treatments.”
Immunotherapies that genetically modulate the antigenic receptors on a patient’s T cells—so-called CAR-T therapy—to seek out and destroy cancer have been met with favorable success over the past several years. Subsequently, CAR-T cells have received all the accolades and attention among genetically modified immune cells. But now there is a new player on the pitch that could give CAR-T a run for its money. Researchers at University of California San Diego School of Medicine and the University of Minnesota report that CAR-modified natural killer (NK) cells derived from human induced pluripotent stem cells (iPSCs) display heightened activity against a mouse model of ovarian cancer.
Early testing of CAR-T therapies has shown promise—and sometimes dramatic success—but there are distinct limitations. First, cells must be isolated from each individual—a process that takes significant time and money. Additionally, since T-cell therapy is designed to work only for that patient, some patients may not be able to have T cells collected, or they may not have time for this process before the tumor progresses. This means some patients who could potentially benefit will not be able to get CAR T-cell–based therapies.
In the current study, the researchers tested CAR-NK cells derived from human iPSCs in an ovarian cancer xenograft mouse model, comparing their antitumor activity against other versions of NK cells and CAR T cells. The former demonstrated similar activity to CAR T cells, but with less toxicity. Kaufman said data indicated ovarian cancer was a good first target, but 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.
“We identified a CAR containing the transmembrane domain of NKG2D, the 2B4 co-stimulatory domain, and the CD3ζ signaling domain to mediate strong antigen-specific NK cell signaling,” the authors wrote. “NK cells derived from human iPSCs that express this CAR (NK-CAR-iPSC-NK cells) have a typical NK cell phenotype and demonstrate improved anti-tumor activity compared with T-CAR-expressing iPSC-derived NK cells (T-CAR-iPSC-NK cells) and non-CAR-expressing cells. In an ovarian cancer xenograft model, NK-CAR-iPSC-NK cells significantly inhibited tumor growth and prolonged survival compared with PB-NK cells, iPSC-NK cells, or T-CAR-iPSC-NK cells.”
“NK cells offer significant advantages, as they don’t have to be matched to a specific patient,” Dr. Kaufman added. “Additionally, one batch of iPSC-derived NK cells can be potentially used to treat thousands of patients, which means we can develop standardized, ‘off-the-shelf’ treatments and use these in combination with other cancer drugs.”
The researchers are now collaborating with scientists from San Diego–based Fate Therapeutics to scale up processes to progress to clinical trials.