Preclinical research suggests that activating the STING pathway may be a feasible approach for treating acute myeloid leukemia (AML).
The STING protein has been shown to play a crucial role in the immune system’s ability to “sense” cancer by recognizing and responding to DNA from tumor cells.
In past studies, researchers injected compounds that activate the STING pathway directly into solid tumors in mice, and this produced potent anti-tumor immune responses.
In a new study, researchers injected substances that mimic tumor-cell DNA into the bloodstream and found they could stimulate STING to provoke a life-extending immune response in mice with AML.
“Delivery of these substances into the blood led to massive immune responses,” said study author Justin Kline, MD, of the University of Chicago in Illinois.
“I’ve worked extensively with animal models of this disease, and have never seen responses like this.”
This research, published in Cell Reports, is the first demonstration that activating the STING pathway could be effective in hematologic malignancies.
STING (short for STimulator of INterferon Genes) plays a role in detecting threats, such as viral infections or cancer. STING is activated when DNA turns up in the wrong place, inside the cell but outside the nucleus.
When it encounters such misplaced DNA, STING induces the production of interferon-beta and other chemical signals that recruit certain components of the immune system to manage the threat, such as leukemia-specific killer T cells.
In this study, the researchers found that mice with established AML were rarely able to launch an effective immune response against the disease.
But when the team exposed the mice to DMXAA (5,6-dimethylxanthenone-4-acetic acid), a molecule that activates STING, the immune system responded aggressively, culminating in the activation of highly potent, cancer-cell killing T cells.
This response prolonged survival and, in some cases, cured the mice of their leukemia. About 60% of DMXAA-treated mice survived long-term. They were even able to protect themselves when “re-challenged” with AML cells.
Because of significant differences between mice and humans, DMXAA does not activate the human STING pathway, but researchers have found that several cyclic dinucleotides—signaling molecules produced by bacteria—have a comparable effect in stimulating the STING pathway.
This leads to an immune response that begins with the production of type I interferons and proceeds to later, more powerful stages, ultimately including leukemia-specific T cells.
“Our results provide strong rationale for the clinical translation of STING agonists as immune therapy for leukemia and possibly other hematologic
malignancies,” said study author Emily Curran, MD, of the University of Chicago.
However, Dr Kline noted that this approach is “not without risk.” He said it can induce “a lot of inflammation, fever, even shock.” Such a stimulated immune system can be “too effective,” especially when the therapy is given through the blood stream, rather than injected into a solid tumor.
“I think drug makers will want to focus on intra-tumoral injection studies before they are ready to bet on systemic infusion,” Dr Kline said. “But this is an important first step.”
