Dual approach puts the sting back in STING therapy

Stimulator of interferon genes, or STING, agonists have enjoyed a bit of buzz over the past 10 years. Takeda, Eisai and other firms are evaluating the innate immune response stimulators in clinical trials in multiple cancer types including advanced solid tumors.

But while STING agonists have shown promise in preclinical research as mono- and adjunctive therapies—enough promise that companies like GSK have inked big deals to develop them—they’ve faltered when it’s time to translate them to the clinic. Now, researchers from the University of North Carolina Lineberger Comprehensive Cancer Center have elucidated a mechanism that might explain why, as well as shown that a dual therapy could improve the drugs’ efficacy.

In a paper published Oct. 5 in Nature, the researchers described how they discovered that activating the STING protein triggered the release of IL-35-positive regulatory B cells. To their surprise, that process reduced the proliferation of natural killer cells, which are key to the immune system’s anti-tumor response. Combining IL-35-blocking antibodies with STING agonists reduced tumor growth more substantially than did treatment with either therapy on its own.

“Previous research indicated that a STING-triggered response may be critical for anti-tumor natural killer cell function,” Sirui Li, PhD, co-first author, explained in a press release. “But our finding provides a previously underappreciated counter-scenario whereby a STING activator induces B regulatory cells to secrete IL-35, which reduces the number of natural killer cells [and suppresses] an anti-tumor response.”

The researchers started with animal models of pancreatic cancer, then expanded their study to include melanoma, triple-negative breast cancer and lung cancer. Their results were consistent across all tumor types and with five different types of STING agonists. The team has now submitted a patent application for the combined therapy and are gearing up to study it in humans.

Though this is the first time researchers have combined an IL-35 antibody with STING agonists to improve efficacy, other dual therapies have been tried. This spring, another research team led by scientists at UC Berkeley found that combining a STING agonist with an IL-2 superkine could “effectively cure” some subtypes of solid tumors.

While the UNC study looked at improving STING agonists' efficacy when used as monotherapies, much of the excitement around them has come from their use with other treatment modalities, such as checkpoint blockade inhibitors. They’ve even been evaluated as an adjunct therapy with CAR-T cells by another team out of UNC.

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