Expression of new antigens on tumor cells by inhibiting nonsense-mediated mRNA decay
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IMMUNOLOGY & MICROBIOLOGY IN MIAMI
Expression of new antigens on tumor cells by inhibiting nonsense-mediated mRNA decay Eli Gilboa
Eli Gilboa
Published online: 6 November 2013 Ó Springer Science+Business Media New York 2013
Abstract The main reason why tumors are not controlled by the immune system of the cancer patient is that tumors do not express potent tumor antigens that can be recognized by the immune system as ‘‘foreign.’’ The current focus in developing immune-based modalities is to potentiate an immune response against the existing, albeit weak, antigens expressed in the tumor. An alternative approach is to express new, and hence potent, antigens in tumor cells in situ. To this end, we have developed an approach to generate new antigenic determinants in tumor cells using siRNA technology to inhibit nonsense-mediated mRNA decay (NMD), a surveillance mechanism which prevents the expression of mRNAs containing a premature termination codon. Targeting siRNA inhibition to tumor cells—an essential requisite because of the constitutive nature and physiological roles of the NMD process—is accomplished by using a novel targeting technology based on using oligonucleotide aptamer ligands. Aptamers or aptamer-targeted siRNA conjugates, unlike antibodies, can be synthesized in a chemical process providing a more straightforward and cost-effective manufacturing and regulatory approval process to generate clinical-grade reagents. In murine tumor models, the aptamer-targeted siRNA-mediated NMD inhibition in tumor cells led to significant inhibition of tumor growth, which was superior to best-in-class ‘‘conventional’’ cancer vaccination protocols. 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 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. Keywords Nonsense-mediated mRNA decay Cancer immunotherapy Tumor antigens Oligonucleotide aptamers Small interfering RNAs
Introduction Studies in murine models have shown that tumors are recognized by the immune system and can elicit an immune response which controls tumor progression. Several lines of evidence, including recent epidemiological studies, strongly suggest that this is also the case in human
E. Gilboa (&) Department of Microbiology and Immunology, Dodson Interdisciplinary Immunotherapy Institute, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA e-mail: [email protected]
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cancer [1–3]. Yet, this naturally occurring tumor-induced immune response is weak and has a limited impact in delaying, but not reversing, tumor progression. A main reason why the naturally occurring antitumor response is weak and ultimately fails to control tumor progression is that, unlike pathogens, tumors do not express
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