CAR-T cell therapies have transformed treatment for several blood cancers, but they have largely been ineffective against solid tumors like pancreatic cancer. These tumors have a dense shield of connective tissue and immune-suppressing cells that prevent therapeutic cells from reaching the cancer. Pancreatic tumors also frequently shift their molecular markers to avoid being recognized by the immune system.

To overcome these defenses, the UCLA team turned to invariant natural killer T cells, or NKT cells — a rare but powerful type of immune cell. They equipped the cells with a chimeric antigen receptor, or CAR, that targets mesothelin, a protein commonly found on pancreatic cancer cells. The engineered NKT cells launched multiple, independent attacks, overwhelming the cancer’s ability to adapt.

“We’re essentially surrounding the tumor with no escape routes,” said first author Yanruide Li, a postdoctoral scholar in the UCLA Broad Stem Cell Research Center Training Program. “Even when the cancer tries to evade one attack pathway by changing its molecular signature, our therapy is hitting it from multiple other angles at the same time. The tumor simply can’t adapt fast enough.”

The therapy was successful even in models targeting the liver, one of the most common and dangerous sites for pancreatic metastasis. Because NKT cells are naturally compatible with any immune system, the therapy can be mass-produced without the lengthy, individualized process required for traditional CAR-T treatments.

Since mesothelin is also found in breast, ovarian, and lung cancers, researchers believe the therapy may eventually be used to treat multiple tumor types. The UCLA team has completed preclinical studies and plans to submit applications to the Food and Drug Administration to begin clinical trials.

If successful in humans, CAR-NKT therapy could offer a much-needed breakthrough against one of the deadliest cancers.