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Recombinant DNA vaccines protect against tumors that are resistant to recombinant vaccinia vaccines containing the same gene

Gene Therapy volume 8, pages 128–138 (2001)Cite this article

Abstract

Antigen-specific cancer immunotherapy involves the delivery of tumor-associated antigen to the host for the generation of tumor-specific immune responses and antitumor effects. We hypothesized that different delivery systems may influence the pattern of antigen-specific immune response and the outcome of antitumor effect. We therefore evaluated recombinant vaccinia virus and naked DNA for the generation of antigen-specific immune responses and antitumor effects. We previously found that recombinant vaccinia and naked DNA vaccines containing the chimeric Sig/E7/LAMP-1 gene were capable of controlling the growth of HPV-16 E7-expressing tumor cells (TC-1). In this study, we performed a head-to-head comparison of optimized delivery of Sig/E7/LAMP-1 vaccinia and DNA vaccines using dose-escalating tumor challenge. At a dose of 1 × 106 TC-1 cells per mouse, Sig/E7/LAMP-1 DNA provided 100% protection against subcutaneous growth of tumors, while Vac-Sig/E7/LAMP-1 protected only 40% of the mice. Furthermore, Sig/E7/LAMP-1 DNA vaccines are capable of protecting against challenge with a more stringent subclone of TC-1 (TC-1 P2) established from TC-1 tumors that survived initial Sig/E7/LAMP-1 vaccinia vaccination. Immunological assays revealed that both vaccines induced comparable levels of CD8+ T cell precursors and anti-E7 antibody titers. Interestingly, Sig/E7/LAMP-1 vaccinia induced both E7-specific IFN-γ- and IL4-secreting CD4+ T cell precursors while Sig/E7/LAMP-1 DNA induced only E7-specific IFN-γ-secreting CD4+ T cell precursors. We also found that IL-4 knockout C57BL/6 mice vaccinated with Sig/E7/LAMP-1 vaccinia exhibited a more potent antitumor effect than vaccinated wild-type C57BL/6 mice in our tumor protection experiments. These results suggest that IL-4 may play a detrimental role in the antitumor effect mediated by vaccinia vaccines. Our findings suggested that DNA vaccines may provide better tumor protection than vaccinia vaccines employing the same gene, which may have implications in the future design of antigen-specific cancer immunotherapy.

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Acknowledgements

We would like to thank Drs Richard Roden and Robert J Kurman for helpful discussions. We thank Dr Ephraim Fuchs for providing C57BL/6 IL-4 knockout mice. We would also like to thank Howard Jen for superb technical assistance. This work was supported by NIH 5 po1 34582–01, U19 CA72108–02, RO1 CA72631–01, the Cancer Research Institute and the Richard W TeLinde endowment.

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Authors and Affiliations

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

    C-H Chen, DM Pardoll & T-C Wu

  2. Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan

    C-H Chen

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

    T-L Wang, H Ji, C-F Hung, W-F Cheng, M Ling & T-C Wu

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

    T-C Wu

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

    T-C Wu

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Chen, CH., Wang, TL., Ji, H. et al. Recombinant DNA vaccines protect against tumors that are resistant to recombinant vaccinia vaccines containing the same gene. Gene Ther 8, 128–138 (2001). https://doi.org/10.1038/sj.gt.3301370

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