Stimulator of interferon genes (STING) is a protein that senses DNA in the cytosol, where it comes from either an infectious invader or a damaged nucleus and sets off an immune response that ultimately results in the activation of T cells.

STING agonists are among the strategies that have been tested in hopes they would increase the response rate to checkpoint blockade.

So far, clinical responses to first-generation STING agonists have been underwhelming.

Part of the issue is that initial STING agonists, which were analogs of the natural STING activator cGAMP, needed to be injected directly into tumors, which limited their utility to certain tumor types.

Hopes of a robust abscopal response similar to that sometimes seen after radiation, where treatment of one tumor leads to a generalized immune response against metastases, have by and large not materialized.

Now, back-to-back papers in the Aug. 21, 2020, issue of Science have detailed the preclinical development of orally available STING agonists.

Scientists at The Scripps Research Institute described identifying SR-717 through a process of screening and optimization, and testing it in mouse models of melanoma, where the compound led to tumor regressions.

A second paper, published by researchers from Merck & Co. Inc., reported that their STING agonist MSA-2 both stimulated tumor regressions on its own and synergized with anti-PD1 therapy in mouse models of colon cancer, a tumor type that usually does not respond well to checkpoint blockade.

If intratumoral injection has not been quite efficacious enough, orally available agonists potentially have the opposite issue, given that STING activation is a ubiquitous innate immune defense mechanism.

“There is definitely a tox problem with this approach,” Luke Lairson told BioWorld.

Lairson is an associate professor of chemistry at The Scripps Research Institute and the senior author of one of the papers, describing the compound SR-717.

Still, his team reported that efficacious doses of SR-717 “despite inducing modest levels of IFN-β,” suggesting that there is a viable therapeutic window.

Interestingly, the Scripps group showed that treatment with their compound induced the expression of PD-L1. That finding, they wrote in their paper, has “important implications for the choice of agent to be combined with a STING agonist, as well as the relative timing of a dosing regimen, in the context of cancer treatment. Presumably, it would be unproductive to treat with an agent that increases the relative abundance of the target of the second agent.”

Both groups reported that their compounds acted on the “closed” structure of STING, which is induced by tumors and the aging process, rather than its open structure, which is a response to infectious agents.

Lairson said that the work’s value lies partly in “the breadth of potential applications.” As with PD-1 blockers themselves, “it’s not a single cancer type” that would be susceptible to STING agonists.

And though part of his team’s plan is to develop SR-717, in collaboration with the California Institute for Biomedical Research (CALIBR), which is TSRI’s translational arm, Lairson also noted that the compound has utility for basic research.

“We think there is potential here to illuminate a host of other STING-related biological processes,” he said.

STING is not the only innate immune signaling mechanism that is being eyed for the clinic. For the time being, Lairson remained agnostic with respect to the relative merits of targeting STING and other innate immune mechanisms such as toll-like receptors (TLRs) and the innate checkpoint molecule CD47, alone or in combination with other agents.

“That’ll have to play out in the clinic,” he said.

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