Putting the 'STING' on CAR-T cells to turn them against breast cancer and other solid tumors

Mouse
Adding STING agonists and checkpoint inhibitors to CAR-T treatments improved the ability of the engineered cells to fight breast cancer in mice, a University of North Carolina study showed. (Pixabay)

The immune pathway known as stimulator of interferon genes (STING) has long been of interest in the oncology community because activating it creates an inflammatory environment that should improve the ability of immune cells to attack cancer. But experimental STING-activating treatments have produced mixed results in clinical trials.

Researchers at the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center have promising evidence that adding STING activators to CAR-T cell therapies could be an effective way to turn the engineered cells against breast cancer. In fact, the combo approach may work in a wide range of solid tumors, they suggested.

Adding STING agonists to CAR-T cells in mouse models of breast cancer significantly slowed tumor growth and improved survival, the UNC team reported in the Journal of Experimental Medicine.

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CAR-T treatments such as Novartis’ Kymriah and Gilead’s Yescarta have been game-changers for some patients with leukemia and lymphoma, but figuring out how to translate the technology to solid tumors has proven challenging.

"We know that CAR-T cells are safe for patients with solid tumors but so far they have not been able to cause significant tumor regression in the overwhelming majority of people treated," said Jonathan Serody, M.D., professor and director of the immunotherapy program at UNC Lineberger, in a statement.

When CAR-T cells migrate to tumors, they typically don’t expand or survive for long periods—a problem that has been linked to the environment surrounding the cancerous masses. In searching for ways to direct CAR-Ts toward solid tumors, Serody and his colleagues zeroed in on two types of cells, Th17 and Tc17, which are known to persist in the tumor microenvironment.

When they combined CAR-Ts generated from Th/Tc17 cells with small-molecule STING agonists, they discovered that the engineered cells persisted for long periods in the tumor microenvironment. Adding inhibitors of immune checkpoints such as PD-1 led to a prolonged attack by the CAR-T cells, the UNC team reported.

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There are multiple STING-targeted therapeutics in clinical trials, and the target has generated some interest in Big Pharma. Merck is working on a combination of its PD-1 inhibitor Keytruda with STING agonist MK-1454. It had initially tried MK-1454 as a monotherapy in solid tumors, with little success.

Novartis teamed up with Aduro Biotech to develop a STING agonist but pulled out of the deal in 2019, citing disappointing clinical results. Aduro ultimately merged with Chinook Therapeutics in a deal focused on renal disease.

Such disappointments haven’t dampened the interest in STING, however. AbbVie is among the biopharma players pursuing the pathway, via its 2019 acquisition of Mavupharma, which is working on STING modulators that its scientists believe will be able to be delivered orally.

The next step for the UNC team is to investigate the CAR-T combination approach in head and neck cancers, they said. They hope to move the therapy into human clinical trials shortly, they added.