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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Liu, M.A., Fu, T.M., Donnelly, J.J., Caulfield, M.J. & Ulmer, J.B. DNA vaccines. Mechanisms for generation of immune responses. Adv. Exp. Med. Biol. 452, 187–191 (1998).
Irvine, K.R., Rao, J.B., Rosenberg, S.A. & Restifo, N.P. Cytokine enhancement of DNA immunization leads to effective treatment of established pulmonary metastases. J. Immunol. 156, 238–245 (1996).
Gurunathan, S. et al. CD40 ligand/trimer DNA enhances both humoral and cellular immune responses and induces protective immunity to infectious and tumor challenge. J. Immunol. 161, 4563– 4571 (1998).
Atkins, G.J., Sheahan, B.J. & Liljestrom, P. Manipulation of the Semliki Forest virus genome and its potential for vaccine construction. Mol. Biotechnol. 5, 33–38 (1996).
Wang, M. et al. Active immunotherapy of cancer with a nonreplicating recombinant fowlpox virus encoding a model tumor-associated antigen. J. Immunol. 154, 4685–4692 (1995).
Rosenberg, S.A. et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nature Med. 4, 321–327 (1998).
Overwijk, W.W. et al. Vaccination with a recombinant vaccinia virus encoding a "self" antigen induces autoimmune vitiligo and tumor cell destruction in mice: requirement for CD4(+) T lymphocytes. Proc. Natl. Acad. Sci. USA 96, 2982–2987 (1999).
Rao, J.B. et al. IL-12 is an effective adjuvant to recombinant vaccinia virus-based tumor vaccines: enhancement by simultaneous B7-1 expression. J. Immunol. 156, 3357–3365 (1996).
Berglund, P., Smerdou, C., Fleeton, M.N., Tubulekas, I. & Liljestrom, P. Enhancing immune responses using suicidal DNA vaccines. Nature Biotechnol. 16, 562–565 (1998).
Miller, D.K. The role of the Caspase family of cysteine proteases in apoptosis. Semin. Immunol. 9, 35–49 (1997).
Chappell, D.B., Zaks, T.Z., Rosenberg, S.A. & Restifo, N.P. Human melanoma cells do not express Fas (Apo-1/CD95) ligand. Cancer Res. 59, 59–62 ( 1999).
Zaks, T.Z., Chappell, D.B., Rosenberg, S.A. & Restifo, N.P. Fas-mediated suicide of tumor-reactive T cells following activation by specific tumor: selective rescue by caspase inhibition. J. Immunol. 162, 3273–3279 (1999).
Hariharan, M.J. et al. DNA immunization against herpes simplex virus: enhanced efficacy using a Sindbis virus-based vector. J. Virol. 72, 950–958 (1998).
Albert, M.L., Sauter, B. & Bhardwaj, N. Dendritic cells acquire antigen from apoptotic cells and induce class I- restricted CTLs. Nature 392, 86–89 (1998).
Specht, J.M. et al. Dendritic cells retrovirally transduced with a model antigen gene are therapeutically effective against established pulmonary metastases. J. Exp. Med. 186, 1213– 1221 (1997).
Der, S.D., Yang, Y.L., Weissmann, C. & Williams, B.R. A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis. Proc. Natl. Acad. Sci. USA 94, 3279–3283 (1997).
Cella, M., Salio, M., Sakakibara, Y., Langen, H., Julkunen, I. & Lanzavecchia, A. Maturation, Activation, and Protection of Dendritic Cells Induced by Double-stranded RNA. J. Exp. Med. 189, 821–829 (1999).
Restifo, N.P. The new vaccines: building viruses that elicit antitumor immunity. Curr. Opin. Immunol. 8, 658–663 (1996).
Pardoll, D.M. Cancer vaccines. Nature Med. 4, 525– 531 (1998).
Rosenberg, S.A. et al. Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens. J. Natl. Cancer Inst. 90, 1894–1900 (1998).
Mandl, C. W., Aberle, J. H, Aberle S. W, Holzmann H, Allison, S. L, and Heinz, F. X. In vitro-synthesized infectious RNA as an attenuated live vaccine in a flavivirus model. Nature Med. 4(12), 1438–1440.(1998).
Dubensky, T. W., Polo, J. M. & Liu, M. A. Live virus vaccines: Something old, something new, something borrowed... Nature Med. 4, 1357– 1358 (1998).
Fink, L. et al. Real-time quantitative RT-PCR after laser-assisted cell picking. Nature Med. 4, 1329–1333 (1998).
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/10548
This article is cited by
-
Cancer vaccine strategies using self-replicating RNA viral platforms
Cancer Gene Therapy (2023)
-
Recent developments of automated flow chemistry in pharmaceutical compounds synthesis
Journal of Flow Chemistry (2023)
-
The non-coding RNA interactome in joint health and disease
Nature Reviews Rheumatology (2021)
-
In vitro evolution of enhanced RNA replicons for immunotherapy
Scientific Reports (2019)