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Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and antitumor effects

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Abstract

We recently demonstrated that Venezuelan equine encephalitis virus-based replicon particle (VRPs) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP-expressing interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and antitumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)), and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12, and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP-IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing antitumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL-12 at the VRP-CEA(6D) injection site provided more potent activation of CEA-specific immune responses than that of VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted.

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Conflict of interest

Peter Berglund, Bolyn Hubby, Whitney Lewis, and Jonathan Smith were previously employed by Alphavax,Inc. Takuya Osada, Michael A. Morse, Donna Niedzwiecki, Xiao Yi Yang, Amy Hobeika, Bruce Burnett, Gayathri R. Devi, Timothy M. Clay, and H. Kim Lyerly have no conflict of interest.

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Authors and Affiliations

  1. Department of Surgery, Duke University Medical Center, Box 2606 MSRB1 Rm 433b Research Dr, Durham, NC, 27710, USA

    Takuya Osada, Xiao Yi Yang, Amy Hobeika, Gayathri R. Devi, Timothy M. Clay & H. Kim Lyerly

  2. Department of Medicine, Duke University Medical Center, Durham, NC, USA

    Michael A. Morse

  3. Department of Immunology, Duke University Medical Center, Durham, NC, USA

    Timothy M. Clay & H. Kim Lyerly

  4. Duke Comprehensive Cancer Center, Durham, NC, 27710, USA

    Michael A. Morse, Donna Niedzwiecki, Bruce Burnett, Gayathri R. Devi, Timothy M. Clay & H. Kim Lyerly

  5. Liquidia Technologies, RTP, Durham, NC, 27709, USA

    Peter Berglund, Bolyn Hubby & Jonathan Smith

  6. Precision Biosciences, Durham, NC, 27701, USA

    Whitney Lewis

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  1. Takuya Osada
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  2. Peter Berglund
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Correspondence to H. Kim Lyerly.

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Osada, T., Berglund, P., Morse, M.A. et al. Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and antitumor effects. Cancer Immunol Immunother 61, 1941–1951 (2012). https://doi.org/10.1007/s00262-012-1248-y

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  • DOI: https://doi.org/10.1007/s00262-012-1248-y

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