Harnessing the immune system is emerging as one of the most promising new ways to fight cancer. Most cancer cells are eliminated by the immune system; however, over a lifetime, a few may escape this immune surveillance and lead to tumors and metastases. Hence a formidable opportunity has been to find ways to make the immune system recognize the tumor as a foreign body and trigger a response. A team of researchers at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine overcame this challenge and developed an entirely new method to induce the expression of antigens (the proteins recognized by the immune system) on the surface of tumor cells, thereby spurring a much more robust immune response. The finding could lead to a new therapy for patients with most forms of cancer, even the more aggressive tumors, in the foreseeable future.
Eli Gilboa, Ph.D., Dodson Professor of Microbiology and Immunology and co-leader of the Tumor Immunology Program at Sylvester, led the study that is being published in the May 13 issue of the journal Nature. The research team consisted of Fernando Pastor, Ph.D., post doctoral associate at Sylvester, Despina Kolonias, M.S., senior research associate at Sylvester, and Paloma Giangrande, Ph.D., assistant professor of internal medicine at the University of Iowa.
Pathogens such as bacteria and viruses elicit an immune response because they express antigens that are recognized as foreign. This response revs up the body’s natural defenses and eliminates the microorganisms. Because tumor cells are similar to normal cells in our bodies, they don’t express many foreign antigens. Therefore, they manage to escape the immune surveillance and grow unchecked to form cancers. Gilboa’s team devised a method to force tumor cells to express new antigens on their surface, making tumors appear more like a “pathogen,” and consequently, to trigger a more potent immune response. “We’ve developed what could become an alternative to vaccines,” says Gilboa, “that would be simpler, broadly applicable, and potentially more effective.”
Normally, DNA information is converted to RNA, which in turn translates into a protein, the final product. During RNA synthesis there is a process known as nonsense mediated mRNA decay which detects and eliminates defective RNAs. If a defect is present, the RNA is degraded and the protein is not formed. However, if the nonsense mediated mRNA process is not functional, the defective RNAs are not degraded and they will generate aberrant proteins, which will be viewed as foreign by the immune system and hence stimulate an immune response. With that in mind, Gilboa and his team focused on inhibiting the RNA degradation process, but only in tumor cells.
Specific proteins are present on the surface of tumor cells, such as PSMA on prostate cancer cells. Using nucleic acid technology, the researchers developed a small interfering RNA (siRNA) which inhibits the nonsense mediated mRNA decay process. The siRNA was then linked to a targeting ligand, also made of nucleic acid called “aptamer” which binds to selected proteins present only on the surface of tumor cells. In this research, it bound to PSMA expressed on prostate tumors. Acting as a missile, the aptamer targets the siRNA to tumor cells and spares normal cells. In mice, it eliminated the tumor.
Joseph Rosenblatt, M.D., professor of medicine and interim director of Sylvester, says Dr. Gilboa has developed a “very clever way of embracing the body’s immune response” and his research “represents a completely new approach to immunotherapy of cancer.”
Pascal J. Goldschmidt, M.D., senior vice president for medical affairs and dean of the UM Miller School of Medicine, describes the work as “groundbreaking and possibly a brand new opportunity for the millions of patients who are victims of cancers.”
Gilboa is the Dodson Professor of Microbiology and Immunology thanks to an extraordinary gift from Eugenia Dodson following her death in 2006. Because of her battle with lung cancer, she dedicated one-third of her $35.6 million estate to be used for cure-focused cancer research at Sylvester.
Gilboa, who worked in vitro and with mice, describes his findings as “a potentially significant discovery toward a new therapy.” The next step, he believes, is clinical trials at the Sylvester Comprehensive Cancer Center. Gilboa says they would likely start with prostate cancer since the reagents are available, but adds that breast cancer expressing HER2 would be another candidate.