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Senior Member
Join Date: Mar 2006
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totally new immunotherapy approach developed
Research Team Develops Novel Strategy to Destroy Tumors Using the Immune System
[University of Miami Health System]
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."
ABSTRACT: Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay
[Nature]
The main reason why tumours are not controlled by the immune system is that, unlike pathogens, they do not express potent tumour rejection antigens (TRAs). Tumour vaccination aims at stimulating a systemic immune response targeted to, mostly weak, antigens expressed in the disseminated tumour lesions. Main challenges in developing effective vaccination protocols are the identification of potent and broadly expressed TRAs and effective adjuvants to stimulate a robust and durable immune response. Here we describe an alternative approach in which the expression of new, and thereby potent, antigens are induced in tumour cells by inhibiting nonsense-mediated messenger RNA decay (NMD). Small interfering RNA (siRNA)-mediated inhibition of NMD in tumour cells led to the expression of new antigenic determinants and their immune-mediated rejection. In subcutaneous and metastatic tumour models, tumour-targeted delivery of NMD factor-specific siRNAs conjugated to oligonucleotide aptamer ligands led to significant inhibition of tumour growth that was superior to that of vaccination with granulocyte-macrophage colony-stimulating factor (GM-CSF)-expressing irradiated tumour cells, and could be further enhanced by co-stimulation. Tumour-targeted NMD inhibition forms the basis of a simple, broadly useful, and clinically feasible approach to enhance the antigenicity of disseminated tumours leading to their immune recognition and rejection. 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.
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