Old chemotherapy drug, new therapy against pancreatic cancer?

The fight against cancer is an arms race, and one of the most powerful weapons in doctors' arsenal is immunotherapy. Immune checkpoint therapy has become the standard of care in several types of cancer. However, the Nobel Prize-winning strategy is ineffective in most patients with pancreatic ductal adenocarcinoma (PDAC).

“Immune checkpoint therapy is only an option in rare cases of PDAC,” says Douglas Fearon, professor at Cold Spring Harbor Laboratory (CSHL). “It is only effective in patients with a specific subtype of PDAC – that's less than 5% of all cases.”

Until recently, it was believed that PDAC did not trigger any immune response. In 2023, Fearon and his team confirmed the opposite. Immune cells attack, but have difficulty penetrating the deadly tumors, allowing PDAC to escape destruction.

Now, Fearon and former CSHL postdoc Jiayun Li have discovered that a common chemotherapy drug called folinic acid weakens the cancer's defenses in mice. They found that folinic acid increases the levels of two anti-cancer immune molecules in PDAC: natural killer T cells (NKT cells) and type I interferons. In mice, this leads to a more effective immune response, slower tumor growth, and longer survival.

The results are published in the journal Proceedings of the National Academy of Sciences.

“We discovered that NKT cells facilitate the production of type I interferon and subsequently cause adaptive immune killing and expansion of T cells,” says Fearon. “T cells respond to tumors but cannot normally enter them if no type I interferon is produced. Folinic acid enhances this response.”

PDAC resists immune cells using a protective shield made of two proteins – CXCR4 and CXCL12. This defensive wall is virtually impenetrable. But when the team treated PDAC tumors with folic acid, cracks became visible. The resulting increased levels of NKT cells and type I interferons acted like signposts, showing a way past PDAC's defenses. Cancer-killing immune cells kept outside the wall were able to enter the tumor and begin the counterattack.

The Fearon lab now aims to translate its discovery into new therapies. They recently partnered with biotechnology company Autobahn Labs to develop potential drugs targeting CXCR4 and CXCL12, which could one day make immune checkpoint therapy a regular option in the fight against PDAC.

“It's been difficult to translate what we've seen in mice to a human therapy,” says Fearon. “But if we're successful, immunotherapy could one day be a viable option for all patients with PDAC – and any other solid tumor – not just the rare cases we see today.”