Researchers at the University of California, San Diego, have discovered that the most common form of liver cancer (with a high mortality rate) can be better targeted and treated using an innovative new stem cell-derived therapy, according to a study recently published in Cellular stem cell.
The treatment, not yet studied in patients, involves laboratory engineering of natural killer (NK) cells, white blood cells that destroy tumor cells, to more effectively combat hepatocellular carcinoma (HCC), one of the most treatment-resistant types of solid tumor.
Genetically modified NK cell therapy does not require customization, like chimeric antigen receptor (CAR) T cell therapy, a relatively new, personalized form of immunotherapy. That means an NK cell therapy could be mass-produced and ready to market for patients, who could begin therapy without delay, their new research shows.
“To some extent, all tumor cells — and perhaps even more so those in hepatocellular carcinoma — suppress the immune cells that try to kill them,” said Professor Dan Kaufman, M.D., Ph.D., of UC San Diego School of Medicine, senior author of the study, director of the Sanford Advanced Therapy Center at the university’s Sanford Stem Cell Institute and a member of the Moores Cancer Center.
“This is a key reason why some immunotherapies like CAR T cells have been less successful in solid tumors than in blood cancers: the immunosuppressive tumor microenvironment.”
Kaufman and his team produced stem cell-derived NK cells in which the receptor for transforming growth factor beta (TGF-β), a protein that affects immune function, was deactivated. Hepatocellular carcinoma tumors and the liver in general contain large amounts of this substance, which inhibits immune cell activity and allows cancer to proliferate.
They found that typical NK cells without the receptor disabled, such as CAR T cells, were not very effective at fighting cancer. “They are pretty resilient tumors; when we put them into mice, they grow and kill the mice,” he said. The five-year survival rate for hepatocellular carcinoma in humans is less than 20 percent.
However, when the researchers tested the modified NK cells against cancer, “we got very good antitumor activity and significantly prolonged survival,” he noted.
“These studies show that blocking transforming growth factor beta is crucial, at least for NK cells, but I think it’s also true for CAR T cells,” Kaufman said. “If you free up NK cells by blocking this inhibitory pathway, they should kill cancer quite effectively.”
Kaufman anticipates that his team’s discovery will manifest itself in clinical trials by many research groups and companies, whether they are working on CAR T-cell or NK cell therapies, combating hepatocellular carcinoma or other challenging types of solid tumors.
“Anyone developing these types of therapies for solid tumors should work to inhibit transforming growth factor beta activity to enhance cancer clearance and achieve effective antitumor activity,” he said.
Co-authors of this study include Jaya Lakshmi Thangaraj, Michael Coffey and Edith Lopez, all of the Division of Regenerative Medicine at UC San Diego School of Medicine.
This work was made possible by NIH/NCI grants U01CA217885, P30CA023100 (administrative supplement) and the Sanford Stem Cell Institute at the University of California, San Diego.