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.