Disclosures: Raghavan reports no relevant financial disclosures.
September 25, 2020
4 min read
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What is STING’s real name?

Disclosures: Raghavan reports no relevant financial disclosures.
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Imagine my surprise when I opened Science last month and was reminded that “Sting” is no longer the sole province of Gordon Matthew Thomas Sumner, CBE — songwriter, singer and bass player extraordinaire, who helped take The Police to fame and fortune with such standards as “Roxanne” and “Walking on the Moon” back in the 20th century.

The newer STING (stimulator of interferon genes) on the block has been around for some years, but has now been reported by two groups who have provided elegant preclinical work that may provide a partial solution to the therapeutic gaps that remain in the PD-1/PD-L1 interface of anticancer therapy.

‘Immunology matters’

For decades it has been clear that immunology matters in the world of oncology (just look at all the grants approved by NCI Study Sections), further supported by myriad studies from Steven A. Rosenberg, MD, PhD, and many others who have nonspecifically stimulated immune function and caused cancers to shrink.

Derek Raghavan

Of course, one should not forget the work of Sir Frank Macfarlane Burnet, OM, AK, KBE, FRS, FAA, FRSNZ, and others who demonstrated that immunosuppression is associated with increased incidence of a range of malignancies, and reversal of that suppression was sometimes associated with tumor regression.

There is no doubt that the new biology of T-lymphocyte activation has been a game changer in the management of hitherto difficult tumors, like melanoma and renal carcinoma, and the antitumor effects of targeting the immune checkpoint interface (PD-1/PD-L1) are now being extended to several malignancies, particularly those of squamous cell derivation.

Despite a great deal of elegant work detailing the function of T cells and the interplay with PD-1/PD-L1 (and associated receptors), it has not been all that clear why T-cell response doesn’t always work.

As summarized elegantly by Gajewski and Higgs in Science, patients with T-cell responsiveness (including histological evidence of T-cell antitumor response) will often fail to gain an anticancer benefit from this phenomenon. Similarly, checkpoint inhibitors will often fail to work when patients have defective innate T-cell function, and there has been real equipoise about whether it makes sense to combine checkpoint inhibitors with chemotherapy, recognizing that cytotoxins may well poison the very cells that the checkpoint inhibitors are attempting to stimulate to anticancer action.

STING experiments

It has been known for some time that the STING pathway is important in the response to infection.

Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) is the natural ligand of the STING protein and causes an activation signaling response that leads to release of interferons and other inflammatory compounds, also with theoretical activity against cancer. Some years ago, STING agonist small molecules were created synthetically but had poor stability, were only modestly active by intratumoral injection in preclinical models and had very limited efficacy in human tumors.

In a detailed report in Science, Chin and colleagues described using a cell-based phenotypic screening approach to identify functioning non-nucleotide small molecule STING agonists. Their lead compound, termed SR-717, has been shown to function as a direct cGAMP mimetic, leading to activation of CD8 T, natural killer and dendritic cells.

In a series of experiments testing parenteral SR-717, the team showed a dose-response relationship for interferon production and clear evidence of growth inhibition of a syngeneic murine B16 melanoma line for both local and metastatic growth. A second STING agonist with different physicochemical properties, SR-301, had a more variable anticancer effect but was shown to be active when administered orally.

In a preliminary communication in the same volume, Pan and colleagues used a broadly based screening algorithm to identify another orally bioavailable inducer of interferon-beta that binds both human and murine STING. Whether administered orally or parenterally, this agent induced regression of a series of murine MC38 colon cancers.

Interestingly, when rechallenged, mice that had undergone tumor regression were resistant to implantation of new tumors. For tumors that were poorly responsive to checkpoint inhibition, the combination of STING agonist plus a PD-1 antibody may have been superior to STING alone, although it is important to note that this report was rather light on detail. Also of interest, in an acidic environment, this agent had apparently improved uptake into tumor tissues and enhanced anticancer effect.

Science will survive

This series of experiments represents yet another potential step forward in increasing the precision, duration and reliability of harnessing the immune response as anticancer therapy.

In the interface between medicine and politics, one does not have to be a genius to understand the benefits of a former national leader with widespread melanoma surviving for years because of the basic and translational science that leveraged checkpoint inhibition.

However, it is important to note that this is not yet a home run. Both reports were quite preliminary at an oncological level, with relatively underpowered (although convincing) tumor response experiments, and there are many details that require amplification — dosage, schedule of delivery, more information on the impact of associated administration of antibodies directed against PD-1 or PD-L1, and the impact of tumor microenvironment.

That said, at a time when science is under such great challenge from many quarters for political reasons, it is refreshing to refocus on fine, systematic experimental work, with clearly defined hypotheses that are tested in objective and rigorous fashion and reported honestly. Therein lies the integrity of biomedical science and the reason it will survive the assaults of those who are ignorant and importune.

References:

Chin EN, et al. Science. 2020;doi:10.1126/science.abb4255.

Gajewski TF and Higgs EF. Science. 2020;doi:10.1126/science.abc6622.

Pan B-S, et al. Science. 2020;doi:10.1126/science.aba6098.

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