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Ii-Key/HER-2/neu(776-90) hybrid peptides induce more effective immunological responses over the native peptide in lymphocyte cultures from patients with HER-2/neu+ tumors

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Abstract

We have demonstrated that coupling an immunoregulatory segment of the MHC class II-associated invariant chain (Ii), the Ii-Key peptide, to a promiscuous MHC class II epitope significantly enhances its presentation to CD4+ T cells. Here, a series of homologous Ii-Key/HER-2/neu(776-90) hybrid peptides, varying systematically in the length of the epitope(s)-containing segment, are significantly more potent than the native peptide in assays using T cells from patients with various types of tumors overexpressing HER-2/neu. In particular, priming normal donor and patient PBMCs with Ii-Key hybrid peptides enhances recognition of the native peptide either pulsed onto autologous dendritic cells (DCs) or naturally presented by IFN-γ-treated autologous tumor cells. Moreover, patient-derived CD4+ T cells primed with the hybrid peptides provide a significantly stronger helper effect to autologous CD8+ T cells specific for the HER-2/neu(435-43) CTL epitope, as illustrated by either IFN-γ ELISPOT assays or specific autologous tumor cell lysis. Hybrid peptide-specific CD4+ T cells strongly enhanced the antitumor efficacy of HER-2/neu(435-43) peptide-specific CTL in the therapy of xenografted SCID mice inoculated with HER-2/neu overexpressing human tumor cell lines. Our data indicate that the promiscuously presented vaccine peptide HER-2/neu(776-90) is amenable to Ii-Key-enhancing effects and supports the therapeutic potential of vaccinating patients with HER-2/neu+ tumors with such Ii-Key/HER-2/neu(776-90) hybrid peptides.

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Authors and Affiliations

  1. Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Avenue, 115 22, Athens, Greece

    Nectaria N. Sotiriadou, Angelos D. Gritzapis, Ioannis F. Voutsas, Michael Papamichail, Sonia A. Perez & Constantin N. Baxevanis

  2. Antigen Express Inc., 100 Barber Avenue, Worcester, MA, 01606-2478, USA

    Nikoletta L. Kallinteris, Eric von Hofe & Robert E. Humphreys

  3. Surgical Clinic “Mitera-Hospital, Erythrou Stavrou 6, Marousi, Greece

    Theodoros Pavlis

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  1. Nectaria N. Sotiriadou
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  2. Nikoletta L. Kallinteris
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  3. Angelos D. Gritzapis
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  4. Ioannis F. Voutsas
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  5. Michael Papamichail
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  6. Eric von Hofe
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  8. Theodoros Pavlis
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  9. Sonia A. Perez
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  10. Constantin N. Baxevanis
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Correspondence to Constantin N. Baxevanis.

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Nectaria N. Sotiriadou and Nikoletta L. Kallinteris have contributed equally to the work.

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Sotiriadou, N.N., Kallinteris, N.L., Gritzapis, A.D. et al. Ii-Key/HER-2/neu(776-90) hybrid peptides induce more effective immunological responses over the native peptide in lymphocyte cultures from patients with HER-2/neu+ tumors. Cancer Immunol Immunother 56, 601–613 (2007). https://doi.org/10.1007/s00262-006-0213-z

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