Molecules were used to block nonsense-mediated RNA decay, as reported in Nature.
A team of researchers report on a novel siRNA-based approach to cancer therapy that triggers the production of new antigens on cancer cells that prompt an immune system attack. They believe that their new technique could provide a more effective alternative to cancer vaccines.
The work was carried out by investigators at the University of Miami Miller School of Medicine’s Sylvester Comprehensive Cancer Center. Their study is published in Nature in a paper titled “Induction of tumor immunity by targeted inhibition of nonsense-mediated mRNA decay.”
The new technology uses specially designed, tumor-targeted siRNA molecules that block cancer cells from carrying out the natural process of degrading defective RNA. Preventing this process of nonsense-mediated mRNA decay (NMD) essentially allows the cells to produce aberrant proteins in situ, which the immune system views as foreign and attacks, explains lead author, Eli Gilboa, Ph.D., Dodson professor of microbiology and immunology and co-leader of the Tumor Immunology Program at Sylvestor.
The major problem with triggering natural immune reactions against cancer cells is that unlike pathogens, cancer cells don’t express potent tumor-rejection antigens (TRAs), the authors state. As a result, tumor vaccination strategies can only aim to stimulate a systemic immune response against mostly weak antigens expressed in disseminated tumor lesions. The main challenges to developing effective vaccination strategies are thus the identification of potent and broadly expressed TRAs and the development of effective adjuvants to stimulate a robust and durable immune response.
As an alternative to trying to boost immune responses to existing antigens on tumors, Dr. Gilboa’s team designed a tumor-targeted aptamer linked to an siRNA that inhibits the NMD inhibition process. The aptamer specifically targeted prostate-specific membrane antigen (PSMA) expressed on prostate cancer cells.
When the aptamer-siRNA construct was tested in cancer-bearing mice, the tumors were eliminated. The technique was also found to be more effective than vaccination using GM-CSF-expressing irradiated syngeneic tumor cells.
“The NMD inhibition strategy described in this study is simple, consisting of a single reagent that can be synthesized by a cell-free chemical process,” the scientists claim. “It obviates the need to identify TRAs or adjuvants and is broadly applicable as it targets a common pathway in all tumors.”
The researchers admit that there is still room to optimize the dose and treatment schedule of their first generation aptamer-siRNAs. Nevertheless, Dr. Gilboa states, the findings represent “a potentially significant discovery towards a new therapy.” The team also notes that it will be useful to see whether NMD antigens are cross-reactive among different tumors and whether there are any obviously dominant antigens induced by NMD inhibition.
“Tumor-targeted NMD inhibition forms the basis of a simple, broadly useful, and clinically feasible approach to enhance the antigenicity of disseminated tumors leading to their immune recognition and rejection,” the team concludes. “The cell-free, chemically synthesized oligonucleotide backbone of aptamer siRNAs reduces the risk of immunogenicity and enhances the feasibility of generating reagents suitable for clinical use.”