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Cancer Immunology, Immunotherapy

, Volume 61, Issue 11, pp 1941–1951 | Cite as

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

  • Takuya Osada
  • Peter Berglund
  • Michael A. Morse
  • Bolyn Hubby
  • Whitney Lewis
  • Donna Niedzwiecki
  • Xiao Yi Yang
  • Amy Hobeika
  • Bruce Burnett
  • Gayathri R. Devi
  • Timothy M. Clay
  • Jonathan Smith
  • H. Kim LyerlyEmail author
Original article

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.

Keywords

Interleukin-12 Cancer vaccine CEA Alphavirus 

Notes

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.

Supplementary material

262_2012_1248_MOESM1_ESM.pptx (1.3 mb)
Supplementary material 1 (PPTX 1377 kb)

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Takuya Osada
    • 1
  • Peter Berglund
    • 5
  • Michael A. Morse
    • 2
    • 4
  • Bolyn Hubby
    • 5
  • Whitney Lewis
    • 6
  • Donna Niedzwiecki
    • 4
  • Xiao Yi Yang
    • 1
  • Amy Hobeika
    • 1
  • Bruce Burnett
    • 4
  • Gayathri R. Devi
    • 1
    • 4
  • Timothy M. Clay
    • 1
    • 3
    • 4
  • Jonathan Smith
    • 5
  • H. Kim Lyerly
    • 1
    • 3
    • 4
    Email author
  1. 1.Department of SurgeryDuke University Medical CenterDurhamUSA
  2. 2.Department of MedicineDuke University Medical CenterDurhamUSA
  3. 3.Department of ImmunologyDuke University Medical CenterDurhamUSA
  4. 4.Duke Comprehensive Cancer CenterDurhamUSA
  5. 5.Liquidia Technologies, RTPDurhamUSA
  6. 6.Precision BiosciencesDurhamUSA

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