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Comparison of HPV DNA vaccines employing intracellular targeting strategies

Gene Therapy volume 11, pages 1011–1018 (2004)Cite this article

Abstract

Intradermal vaccination via gene gun efficiently delivers DNA vaccines into dendritic cells (DCs) of the skin, resulting in the activation and priming of antigen-specific T cells in vivo. In the context of DNA vaccines, we previously used the gene gun approach to test several intracellular targeting strategies that are able to route a model antigen, such as the human papillomavirus type-16 (HPV-16) E7, to desired subcellular compartments in order to enhance antigen processing and presentation to T cells. These strategies include the use of the sorting signal of lysosome-associated membrane protein (LAMP-1), Mycobacterium tuberculosis heat-shock protein 70 (HSP70), calreticulin (CRT) and the translocation domain (dII) of Pseudomonas aeruginosa exotoxin A (ETA). Vaccination with DNA vaccines encoding E7 antigen linked to any of these molecules all led to a significant enhancement of E7-specific CD8+ T-cell immune responses and strong antitumor effects against an E7-expressing tumor, TC-1. However, we were interested in identifying the most potent DNA vaccine for our future clinical trials. Thus, we performed a series of experiments to directly compare the potency of the various DNA vaccines. Among the DNA vaccines we tested, we found that vaccination with pcDNA3-CRT/E7 generated the highest number of E7-specific CD8+ T cells and potent long-term protection and treatment effects against E7-expressing tumors in mice. Interestingly, we observed that pcDNA3-CRT/E7 is also capable of protecting against an E7-expressing tumor with downregulated MHC class I expression, a common feature associated with most HPV-associated cervical cancers. Our data suggest that the DNA vaccine linking CRT to E7 (CRT/E7) may be a suitable candidate for human trials for the control of HPV infections and HPV-associated lesions.

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Acknowledgements

We thank Drs Robert J Kurman, Keerti V Shah and Drew M Pardoll for helpful discussions. We also thank Drs Ralph Hruban, Ken-Yu Lin, and Richard Roden for critical review of the manuscript. This work was supported by the National Cancer Institute, the American Cancer Society, and Genencor International Inc. T-C Wu received consultation fee, stock option, and sponsored research support from Genecor International Inc. Under separate licensing agreements between Genencor International and the Johns Hopkins University and Cerus Corporation and the Johns Hopkins University, Dr Wu is entitled to a share of royalty received by the University on sales of products described in this article. Dr Wu is a paid consultant to Genencor International and Cerus Corporation. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

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  1. Contributed equally to this paper

Authors and Affiliations

  1. Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    J W Kim, C-F Hung, J Juang, L He, T Woo Kim, C-T Lin, D A Boyd & T-C Wu

  2. Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    D K Armstrong & T-C Wu

  3. Department of Otolaryngology-Head & Neck Surgury, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    S I Pai

  4. Department of Medicine, National Taiwan University, Taipei, Taiwan

    P-J Chen

  5. Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan

    C-T Lin

  6. Department of Obstetrics and Gynecology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu

  7. Department of Molecular Microbiology and Immunology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu

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  1. J W Kim
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Kim, J., Hung, CF., Juang, J. et al. Comparison of HPV DNA vaccines employing intracellular targeting strategies. Gene Ther 11, 1011–1018 (2004). https://doi.org/10.1038/sj.gt.3302252

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