Study: Intermetallic nanoassemblies potentiate systemic STING activation (DOI: 10.1126/science.adx1893)
A research team led by the University of Michigan College of Pharmacy and the University of Texas MD Anderson Cancer Center has developed a new type of nanoparticle therapy that could make cancer immunotherapy safer and more effective.
The researchers say they've created a promising new treatment called CRYSTAL, short for Crystal-like STING-Activating nanoassemblies, by engineering a new nanoparticle that moves through the blood safely to target tumors but without triggering inflammation, which can lead to a range of negative side effects.
Their discovery, which they say represents the next generation of immunotherapies and signals a new way of thinking about medicine design (that is, how the drug is built is as important as what it's made of), is detailed in a research article published in Science.
The study focused on the human immune system's natural tools that recognize and destroy cancer cells. One important pathway is called cGAS-STING, which acts like an alarm system detecting danger and triggering responses that help the body attack tumors. Scientists have long tried to harness the pathway and limit its downsides, such as overstimulation of the immune system and the need for direct injection to tumors.
"While the STING pathway is very powerful, turning it on safely in patients has been a major challenge," said senior author James Moon, the J. G. Searle Professor of Pharmaceutical Sciences at the U-M College of Pharmacy. "We wanted to find a way to strongly activate the immune system without causing harmful side effects."
Moon and colleagues found a solution by using manganese, a naturally occurring metal, to organize small immune-activating molecules into tiny, highly ordered particles. They then coated them with a fatty layer to enable them to travel safely through the bloodstream.
CRYSTAL produced a strong, sustained immune activation at doses far lower than those required for conventional approaches. The findings highlight the possibilities of nutritional elements, in this case manganese, in cancer treatment.
The researchers tested the new nanoparticle across multiple tumor models, including advanced triple-negative breast cancer in vivo.
Preclinical studies showed that CRYSTAL nanoparticles sparked a powerful immune response that reduced or eliminated tumors-even large, advanced ones-without triggering the cytokine storm seen with other forms of immunotherapy. That storm can lead to side effects like inflammation and weight loss.
"We are achieving immune activation without systemic immune inflammation," Moon said. "This is the first time we're seeing such responses. We're very excited about that."
The researchers say the work represents a new way of thinking about medicine design and the next generation of immunotherapies. In addition to improving cancer treatments, they believe this approach may also be applied to other immune-related diseases.
"Our findings show that how a drug is built can be just as important as what it is made of," said first author Xingwu Zhou, a graduate student in pharmaceutical sciences. "By arranging these molecules in a precise way, we can change how they behave in the body."
The findings result from a five-year collaboration among nearly 30 researchers with funding from the National Institute of Dental and Craniofacial Research, National Cancer Institute, U-M Rogel Cancer Center, and UT MD Anderson. The project was one of five funded by the Frankel Innovation Initiative at Michigan Medicine.
"This work highlights how nutritional elements can be harnessed to fine-tune the magnitude of type-I interferon activation, a primary defense system evolutionarily conserved from humans to sea urchins," said Yu Leo Lei, a longtime collaborator formerly at the U-M School of Dentistry and now associate professor of head and neck surgery at UT MD Anderson.
Lei's group has made seminal contributions to the fundamental understanding of how metabolism and nutritional elements regulate the STING-IFN-I pathway and to the development of critical, high-fidelity head and neck squamous cell carcinoma models to test the efficacy of CRYSTAL.
The research team also includes scientists from the U-M Medical School, School of Dentistry and College of Engineering, and Michigan State University.
The technology has been licensed with the help of U-M Innovation Partnerships to Saros Therapeutics and is advancing toward clinical development. In addition to improving cancer treatments, researchers believe this approach may also be applied to other immune-related diseases.
Moon and the University of Michigan have a financial interest in Saros Therapeutics.
