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Stem cell-derived therapy shows promise against treatment-resistant liver cancer

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Researchers at University of California San Diego have found 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-derived therapy.

The treatment, not yet studied in patients, involves the lab engineering of natural killer (NK) cells — white blood cells that destroy tumour cells — to more effectively battle hepatocellular carcinoma (HCC), one of the most treatment-resistant types of solid tumor.

Genetically modified NK-cell therapy doesn’t require personalisation like chimeric antigen receptor (CAR)-expressing T-cell therapy — a relatively new, personalised form of immunotherapy.

That means an NK-cell therapy could be mass produced and shelf-ready for patients, who could begin therapy without delay, their new research shows.

UC San Diego School of Medicine Professor Dan Kaufman, M.D., Ph.D. is lead author on the study, director of the Sanford Advanced Therapy Center at the university’s Sanford Stem Cell Institute and Moores Cancer Center member.

He said: “To some extent all tumour cells — perhaps hepatocellular carcinoma more so — inhibit immune cells that try to kill them,” said

“This is one key reason why some immunotherapies like CAR T cells have been less successful for solid tumors than for blood cancers — the immunosuppressive tumour 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 impairs immune function — was disabled.

HCC tumours and the liver in general contain copious amounts of the substance, which both inhibits the immune cell activity and allows cancer to proliferate.

They found that typical NK cells without the disabled receptor, like CAR T cells, were not very effective in battling the cancer.

Kaufman said: “These are pretty resistant tumours — when we put them in mice, they grow and kill the mice.”

The five-year survival rate for HCC in humans is less than 20 per cent.

When researchers tested the modified NK cells against the cancer, however, “we got very good anti-tumour activity and significantly prolonged survival,” he Kaufman noted.

He added: “These studies demonstrate that it is crucial to block transforming growth factor beta — at least for NK cells, but I also think it’s true for CAR T cells.

“If you unleash NK cells by blocking this inhibitory pathway, they should kill cancer quite nicely.”

Kaufman anticipates that his team’s discovery will manifest itself in the clinical trials of many research groups and companies — whether they’re working on CAR T-cell or NK-cell therapies, battling hepatocellular carcinoma or other challenging types of solid tumours.

The researcher said: “Anyone developing such therapies for solid tumours should be working to inhibit transforming growth factor beta activity to improve cancer-killing and attain effective anti-tumour activity.”

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