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Intramuscular gene transfer of soluble B7.1/IgG1 fusion cDNA induces potent antitumor immunity as an adjuvant for DNA vaccination

Cancer Gene Therapy volume 10, pages 491–499 (2003)Cite this article

Abstract

Soluble B7.1/IgG Fc fusion protein, which has costimulatory effects, is an effective molecular adjuvant in tumor immune therapy. Here, we describe a nonviral intramuscular (i.m.) gene transfer method to deliver this therapeutic protein. Gene transfer was greatly enhanced by electroporation and highly efficient production of this protein was achieved. Serum levels reached up to 1 μg/ml with considerable length of expression and without apparent systemic adverse effects. Lymphocytes from mice coinjected with soluble B7.1/IgG1 and carcinoembryonic antigen (CEA)-encoding plasmids showed significantly elevated CEA-stimulated proliferation, cytokine production, and cytotoxic T-lymphocyte (CTL) activity. These mice gained significant protection against a CEA-positive transplanted tumor, in terms of reduced tumor incidence and growth. The effects were superior when soluble B7.1/IgG1 was expressed as compared to membrane-bound wild-type B7.1. Notably, expression of soluble B7.1/IgG1 alone did not induce any protection against tumor, confirming its primary role as a costimulatory molecule rather than a direct antitumor agent. The plasmid encoding B7.1/IgG1 did not have to be injected at the same site as the antigen-encoding plasmid to exert its adjuvant effect, indicating that circulating protein was sufficient. Muscle histopathology revealed minimal damage to DNA-injected muscles. Importantly, we show that, after gene transfer, muscle tissue can produce this protein in large quantity to exert its immune costimulatory effect for cancer therapy and it would be otherwise difficult and expensive to maintain this high a level of recombinant protein.

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Acknowledgements

This study was funded by the National Cancer Institute of Canada (NCIC). Zheng F Zhou is a recipient of a postgraduate scholarship from the Natural Science and Engineering Research Council of Canada (NSERC). We thank Dr Fawaz Halwani for assistance with FACS analyses, and Dr Keli Song for helpful advice during the course of this study. We also thank Dr Abraham Fuks (McGill University, Canada) for kindly providing reagents and the B18 hybridoma cell line.

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Authors and Affiliations

  1. Department of Pathology, McGill University, Montréal, H3A 2B4, Québec, Canada

    Zheng F Zhou, Yoav Peretz, Yigang Chang, Xiaoying Li & Gérald J Prud'homme

  2. Department of Medicine, McGill University, Montréal, H3A 2B4, Québec, Canada

    Deng Shun Miao

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  1. Zheng F Zhou
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Correspondence to Gérald J Prud'homme.

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Zhou, Z., Peretz, Y., Chang, Y. et al. Intramuscular gene transfer of soluble B7.1/IgG1 fusion cDNA induces potent antitumor immunity as an adjuvant for DNA vaccination. Cancer Gene Ther 10, 491–499 (2003). https://doi.org/10.1038/sj.cgt.7700595

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