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Cancer therapy using a self-replicating RNA vaccine

Abstract

'Naked' nucleic acid vaccines are potentially useful candidates for the treatment of patients with cancer1,2,3, but their clinical efficacy has yet to be demonstrated. We sought to enhance the immunogenicity of a nucleic acid vaccine by making it 'self-replicating'. We accomplished this by using a gene encoding an RNA replicase polyprotein derived from the Semliki forest virus, in combination with a model antigen. A single intramuscular injection of a self-replicating RNA immunogen elicited antigen-specific antibody and CD8+ T-cell responses at doses as low as 0.1 μg. Pre-immunization with a self-replicating RNA vector protected mice from tumor challenge, and therapeutic immunization prolonged the survival of mice with established tumors. The self-replicating RNA vectors did not mediate the production of substantially more model antigen than a conventional DNA vaccine did in vitro. However, the enhanced efficacy in vivo correlated with a caspase-dependent apoptotic death in transfected cells. This death facilitated the uptake of apoptotic cells by dendritic cells, providing a potential mechanism for enhanced immunogenicity. Naked, non-infectious, self-replicating RNA may be an excellent candidate for the development of new cancer vaccines.

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Figure 1: Structure, function and immunogenicity of self-replicating RNA vaccines.
Figure 2: Anti-tumor effects mediated by self-replicating RNA vaccines.
Figure 3: Induction of apoptotic death of host cells by self-replicating RNA and its effect on the uptake by dendritic cells.

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Acknowledgements

The authors thank S.A. Rosenberg for reading the manuscript and for discussions, A. Atwood for help with vector construction, T. Dubensky (Chiron) for advice, M. Blalock for graphics, P. Spiess for help with animal experiments, and S. Wolf (Genetics Institute) for his gift of rmIL-12.

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Correspondence to Nicholas P. Restifo.

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Ying, H., Zaks, T., Wang, RF. et al. Cancer therapy using a self-replicating RNA vaccine. Nat Med 5, 823–827 (1999). https://doi.org/10.1038/10548

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