Vaccination with human anti-trastuzumab anti-idiotype scFv reverses HER2 immunological tolerance and induces tumor immunity in MMTV.f.huHER2(Fo5) mice

Breast Cancer Res. 2011 Feb 4;13(1):R17. doi: 10.1186/bcr2826.

Abstract

Introduction: Novel adjuvant therapies are needed to prevent metastatic relapses in HER2-expressing breast cancer. Here, we tested whether trastuzumab-selected single-chain Fv (scFv) could be used to develop an anti-idiotype-based vaccine to inhibit growth of HER2-positive tumor cells in vitro and in vivo through induction of long-lasting HER-specific immunity.

Methods: BALB/c mice were immunized with anti-trastuzumab anti-idiotype (anti-Id) scFv (scFv40 and scFv69), which mimic human HER2. Their sera were assessed for the presence of HER2-specific Ab1' antibodies and for their ability to reduce viability of SK-OV-3 cells, a HER2-positive cancer cell line, in nude mice. MMTV.f.huHER2(Fo5) transgenic mice were immunized with scFv40 and scFv69 and, then, growth inhibition of spontaneous HER2-positive mammary tumors, humoral response, antibody isotype as well as splenocyte secretion of IL2 and IFN-γ were evaluated.

Results: Adoptively-transferred sera from BALB/c mice immunized with scFv40 and scFv69 contain anti-HER2 Ab1' antibodies that can efficiently inhibit growth of SK-OV-3 cell tumors in nude mice. Similarly, prophylactic vaccination with anti-Id scFv69 fully protects virgin or primiparous FVB-MMTV.f.huHER2(Fo5) females from developing spontaneous mammary tumors. Moreover, such vaccination elicits an anti-HER2 Ab1' immune response together with a scFv69-specific Th1 response with IL2 and IFN-γ cytokine secretion.

Conclusions: Anti-trastuzumab anti-Id scFv69, used as a therapeutic or prophylactic vaccine, protects mice from developing HER2-positive mammary tumors by inducing both anti-HER2 Ab1' antibody production and an anti-HER2 Th2-dependent immune response. These results suggest that scFv69 could be used as an anti-Id-based vaccine for adjuvant therapy of patients with HER2-positive tumors to reverse immunological tolerance to HER2.

MeSH terms

  • Animals
  • Antibodies, Anti-Idiotypic / blood
  • Antibodies, Anti-Idiotypic / immunology*
  • Antibodies, Monoclonal, Humanized / immunology*
  • CHO Cells
  • Cancer Vaccines / immunology*
  • Cell Line, Tumor
  • Cell Survival / immunology
  • Cricetinae
  • Female
  • HEK293 Cells
  • Humans
  • Immune Tolerance*
  • Immunity, Humoral
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mice, Transgenic
  • Ovarian Neoplasms / immunology*
  • Ovarian Neoplasms / therapy
  • Receptor, ErbB-2 / immunology*
  • Single-Chain Antibodies / immunology*
  • Th1 Cells / immunology
  • Th2 Cells / immunology
  • Trastuzumab

Substances

  • Antibodies, Anti-Idiotypic
  • Antibodies, Monoclonal, Humanized
  • Cancer Vaccines
  • Single-Chain Antibodies
  • Receptor, ErbB-2
  • Trastuzumab