Induction of potent CD4⁺ T cell‐mediated antitumor responses by a helper HER‐2/neu peptide linked to the Ii‐Key moiety of the invariant chain

Abstract

The Ii-Key fragment from the MHC class II-associated invariant chain (or Ii protein) has been shown to facilitate direct charging of MHC class II epitopes to the peptide binding groove. The purpose of the present study was to test the potential of a series of Ii-Key/ HER-2/neu(776-790) hybrid peptides to generate increased frequencies of peptide-specific CD4 1 T cells over the native peptide in mice transgenic (Tg) for a chimeric human mouse class II molecule (DR4-IE) (H-2 b ) as well as their antitumor potency. Following in vivo priming, such hybrid peptides induced increased proliferation and frequencies of IFN-c producing CD41 T cells in response to either syngeneic dendritic cells pulsed with native peptide, or HLA-DR4 1 human tumor cell lines expressing HER-2/neu. Hybrid peptides were more stable in an off-rate kinetics assay compared to the native peptide. In addition, antigen-specific

A new era in anticancer peptide vaccines

“…41,42 We also observed strong immunogenicity with HER-2/neu(776-790), which is an extended analog of the p776 to p788 peptide. [43][44][45] CD4-positive T cells primed with the p776 to p790 peptide exhibited an extensive capacity to synergize with syngeneic CTLs for the rejection of HER-2/neu-positive tumors. [43][44][45] Both the p776 to p790 peptide and the p776 to p788 peptide encompass in their sequences the nonamers GVGSPYVSRL (p776-p784), VGSPYVSRL (p777-p785), and PYVSRLLGI (p780-788), which bind with intermediate to high affinity to the HLA-A2.1/A68, HLA-A11, and HLA-A3 alleles, respectively.…”

“…[43][44][45] CD4-positive T cells primed with the p776 to p790 peptide exhibited an extensive capacity to synergize with syngeneic CTLs for the rejection of HER-2/neu-positive tumors. [43][44][45] Both the p776 to p790 peptide and the p776 to p788 peptide encompass in their sequences the nonamers GVGSPYVSRL (p776-p784), VGSPYVSRL (p777-p785), and PYVSRLLGI (p780-788), which bind with intermediate to high affinity to the HLA-A2.1/A68, HLA-A11, and HLA-A3 alleles, respectively. Thus, the p776 to p790 peptide may function as a multipeptide vaccine that contains overlapping T h and CTL epitope motifs, thereby acting as a powerful inducer of antitumor immune responses.…”

“…In several studies, IiKey hybrid peptides demonstrated significantly increased potency over the unmodified epitope peptide in both in vitro and in vivo vaccine studies as determined by the antigen-specific stimulation of T cells. 43 By using the Ii-Key/ HER-2/neu(776-790) peptide, a series of Ii-Key/epitope hybrids were designed and screened in vitro using peripheral blood mononuclear cells from cancer patients who had various types of HER-2-positive tumors to identify a candidate hybrid (AE37) for clinical trials. 43,45 Furthermore, CD4-positive T cells from AE37-immunized mice potentiated CD8-positive T cells to recognize and lyse autologous tumor cells more efficiently in vitro 43,45 and in vivo.…”

“…43 By using the Ii-Key/ HER-2/neu(776-790) peptide, a series of Ii-Key/epitope hybrids were designed and screened in vitro using peripheral blood mononuclear cells from cancer patients who had various types of HER-2-positive tumors to identify a candidate hybrid (AE37) for clinical trials. 43,45 Furthermore, CD4-positive T cells from AE37-immunized mice potentiated CD8-positive T cells to recognize and lyse autologous tumor cells more efficiently in vitro 43,45 and in vivo. [45][46][47] All of the aforementioned studies paved the way for clinical trials of AE37 in patients with breast cancer.…”

Peptide Vaccination Breaks Tolerance to HER-2/neuby Generating Vaccine-Specific FasL+ CD4+ T Cells: First Evidence for Intratumor Apoptotic Regulatory T Cells

“…Here, we evaluate the use of a vaccine mixture consisting of two immunogenic peptides corresponding to the HER-2 (776-790) (p776) CTL epitope (12)(13)(14)(15)(16) and the promiscuous p776 helper T cells (Th) epitope (17)(18)(19)(20)(21). This is the first study, to our knowledge, defining the in vivo effect of combined vaccination with two HER-2/neu peptides representing CTL and Th epitopes on the dynamic relationship between vaccine-specific CTL and Th/Tregs in HER-2/neu tolerant A2.1/DR1 × neuT + and nontolerant A2.1/DR1 × neuT − littermates.…”