Recent approach uses the tumor’s own machinery to supply immune-stimulating molecules

By encouraging cancer cells to supply a molecule that prompts a signaling pathway in nearby immune cells, MIT researchers have found a solution to force tumors to trigger their very own destruction.

Activation of this signaling pathway, referred to as the cGAS-STING pathway, worked even higher when combined with existing signaling pathways Immunotherapy Drugs referred to as checkpoint blockade inhibitors in a study in mice. With this double treatment, tumor growth could possibly be successfully controlled.

The researchers activated the cGAS-STING pathway in immune cells using messenger RNA delivered to cancer cells. This approach can avoid the unwanted effects of administering large doses of a STING activator and utilizes a natural process within the body. This might make it easier to develop a treatment to be used in patients, the researchers say.

“Our approach harnesses the tumor’s own machinery to supply immune-stimulating molecules to generate a potent antitumor response,” says Natalie Artzi, senior research scientist at MIT’s Institute for Medical Engineering and Science, associate professor of drugs at Harvard Medical School, core faculty member at Harvard’s Wyss Institute for Biologically Inspired Engineering and senior writer of the study.

“By increasing cGAS levels in cancer cells, we will improve delivery efficiency – in comparison with targeting the rarer immune cells within the tumor microenvironment – ​​and stimulate the natural production of cGAMP, which then prompts immune cells locally,” she says. “This strategy not only enhances antitumor immunity but additionally reduces the toxicity related to direct administration of STING agonists, bringing us one step closer to safer and more practical cancer immunotherapies.”

Alexander Cryer, visiting researcher at IMES, is the lead writer of the article, which appears this week in .

Immune activation

STING (short for Stimulator of Interferon Genes) is a protein that helps trigger immune responses. When STING is activated, it activates a pathway that initiates the production of type 1 interferons, that are cytokines that stimulate immune cells.

Many research groups, including Artzi’s, have investigated the potential for artificially stimulating this pathway with molecules called STING agonists, which could help immune cells recognize and attack tumor cells. This approach has worked well in animal models but has had limited success in clinical trials, partially since the doses required could cause harmful unwanted effects.

While working on a project exploring recent ways to deliver STING agonists, Cryer became curious when he learned from previous work that cancer cells can produce a STING activator called cGAMP. The cells then secrete cGAMP, which may activate neighboring immune cells.

A part of my philosophy of science is that I actually enjoy taking endogenous processes that the body already has and attempting to use them in a rather different context. Evolution did all of the labor. We just have to work out easy methods to push it in a special direction. Once I saw that cancer cells were producing this molecule, I believed: Possibly there may be a solution to speed up this process.”

Alexander Cryer, visiting scientist at IMES, lead writer of the article

In cells, the production of cGAMP is catalyzed by an enzyme called cGAS. To get tumor cells to activate STING in immune cells, the researchers developed a solution to deliver messenger RNA that encodes cGAS. When this enzyme detects double-stranded DNA within the cell body, which could be a sign of infection or cancer-related damage, it begins producing cGAMP.

“It’s just that cancer cells, because they divide so quickly and never very precisely, are likely to have more double-stranded DNA fragments than healthy cells,” says Cryer.

The tumor cells then release cGAMP into the tumor microenvironment, where it may be taken up by neighboring immune cells and activate their STING signaling pathway.

Tumors in sight

Using a mouse model from Melanomathe researchers evaluated the potential of their recent technique to kill cancer cells. They injected mRNA encoding cGAS encapsulated in lipid nanoparticles into tumors. One group of mice received this treatment alone, while one other received a checkpoint blockade inhibitor and a 3rd group received each treatments.

Administered alone, cGAS and the checkpoint inhibitor each significantly slowed tumor growth. Nevertheless, the very best results were observed within the mice that received each treatments. On this group, tumors were completely eliminated in 30 percent of the mice, while within the groups that received just one treatment, not one of the tumors were completely eliminated.

Evaluation of the immune response showed that mRNA treatment stimulated the production of interferon in addition to many other immune signaling molecules. Quite a lot of immune cells, including macrophages and dendritic cells, were activated. These cells help stimulate T cells, which may then destroy cancer cells.

The researchers were capable of elicit these responses with only a small dose of cGAMP produced by cancer cells, which could help overcome certainly one of the potential obstacles to using cGAMP alone as a therapy: large doses are required to stimulate an immune response, and these doses can result in widespread reactions inflammationTissue damage and autoimmune reactions. When injected alone, cGAMP tends to spread throughout the body and is quickly cleared from the tumor, whereas on this study, the mRNA nanoparticles and cGAMP remained on the tumor site.

“The unwanted effects of this class of molecules might be quite severe, and certainly one of the potential benefits of our approach is that chances are you’ll have the option to suppress some toxicities that may occur once you administer the free molecules,” says Cryer.

The researchers now hope to work on adapting the delivery system in order that it may be administered as a systemic injection reasonably than injecting it into the tumor. Additionally they plan to check mRNA therapy together with DNA-damaging chemotherapy drugs or radiation therapy, which could make the therapy even more practical by potentially making much more double-stranded DNA available to assist activate cGAMP synthesis.