Researchers from the University of California San Diego have discovered that the most common form of liver cancer, one with a high mortality rate, can be better targeted and treated using an innovative new stem cell therapy, according to a study recently published in Cell Stem Cell.
The treatment, which has not yet been studied in patients, involves engineering natural killer (NK) cells (white blood cells that destroy tumor cells) in the laboratory to more effectively combat hepatocellular carcinoma (HCC), one of the most treatment-resistant types of solid tumors.
Genetically modified NK cell therapy does not require personalization like chimeric antigen receptor (CAR)-expressing T cell therapy — a relatively new, personalized form of immunotherapy. That means NK cell therapy can be mass-produced and ready for patients to begin therapy without delay, their new study shows.
“To some extent, all tumor cells, and perhaps most notably hepatocellular carcinoma, inhibit immune cells that are trying to kill them,” said Dan Kaufman, MD, PhD, lead 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 major reason why some immunotherapies, such as CAR T cells, are less successful in solid tumors than in blood cancers: the immunosuppressive tumor microenvironment.”
Kaufman and his team generated stem cell-derived NK cells in which the receptor for transforming growth factor beta (TGF-β) — a protein that disrupts immune function — had been knocked out. HCC tumors and the liver in general contain large amounts of the substance, which both inhibits immune cell activity and allows cancer to proliferate.
They found that typical NK cells without the receptor disabled, like CAR T cells, were not very effective at fighting cancer. “These are pretty resistant tumors — if we put them in mice, they grow and kill the mice,” he said. The five-year survival rate for HCC in humans is less than 20 percent.
However, when researchers tested the modified NK cells against cancer, “we found very good antitumor activity and significantly longer survival,” he noted.
“These studies show that blocking transforming growth factor beta is critical — at least for NK cells, but I think it's true for CAR T cells as well,” Kaufman said. “If you unleash NK cells by blocking this inhibitory pathway, they should be very good at killing cancer.”
Kaufman expects his team's discovery to feed into clinical trials by many research groups and companies, whether they're working on CAR T-cell or NK-cell therapies, or fighting hepatocellular carcinoma or other challenging types of solid tumors.
“Anyone developing such therapies for solid tumors should work on inhibiting the activity of transforming growth factor beta to improve cancer control and achieve effective antitumor activity,” he said.
Co-authors of this study are Jaya Lakshmi Thangaraj, Michael Coffey and Edith Lopez, all in the Division of Regenerative Medicine at UC San Diego School of Medicine.
This work was supported by NIH/NCI grants U01CA217885, P30CA023100 (administrative supplement), and the Sanford Stem Cell Institute at the University of California San Diego.
