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Induction of protective immune responses against NXS2 neuroblastoma challenge in mice by immunotherapy with GD2 mimotope vaccine and IL-15 and IL-21 gene delivery.

Abstract
The GD2 ganglioside expressed on neuroectodermal tumor cells is weakly immunogenic in tumor-bearing patients and induces predominantly IgM antibody responses in the immunized host. Using a syngeneic mouse challenge model with GD2-expressing NXS2 neuroblastoma, we investigated novel strategies for augmenting the effector function of GD2-specific antibody responses induced by a mimotope vaccine. We demonstrated that immunization of A/J mice with DNA vaccine expressing the 47-LDA mimotope of GD2 in combination with IL-15 and IL-21 genes enhanced the induction of GD2 cross-reactive IgG2 antibody responses that exhibited cytolytic activity against NXS2 cells. The combined immunization regimen delivered 1 day after tumor challenge inhibited subcutaneous (s.c.) growth of NXS2 neuroblastoma in A/J mice. The vaccine efficacy was reduced after depletion of NK cells as well as CD4(+) and CD8(+) T lymphocytes suggesting involvement of innate and adaptive immune responses in mediating the antitumor activity in vivo. CD8(+) T cells isolated from the immunized and cured mice were cytotoxic against syngeneic neuroblastoma cells but not against allogeneic EL4 lymphoma, and exhibited antitumor activity after adoptive transfer in NXS2-challenged mice. We also demonstrated that coimmunization of NXS2-challenged mice with the IL-15 and IL-21 gene combination resulted in enhanced CD8(+) T cell function that was partially independent of CD4(+) T cell help in inhibiting tumor growth. This study is the first demonstration that the mimotope vaccine of a weakly immunogenic carbohydrate antigen in combination with plasmid-derived IL-15 and IL-21 cytokines induces both innate and adaptive arms of the immune system leading to the generation of effective protection against neuroblastoma challenge.
AuthorsAleksandra Kowalczyk, Andrzej Wierzbicki, Margaret Gil, Barbara Bambach, Yutaro Kaneko, Hanna Rokita, Elizabeth Repasky, Robert Fenstermaker, Martin Brecher, Michael Ciesielski, Danuta Kozbor
JournalCancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 56 Issue 9 Pg. 1443-58 (Sep 2007) ISSN: 0340-7004 [Print] Germany
PMID17597331 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Cancer Vaccines
  • Gangliosides
  • Interleukin-15
  • Interleukins
  • ganglioside, GD2
  • Interferon-gamma
  • interleukin-21
Topics
  • Animals
  • CD4-Positive T-Lymphocytes (immunology)
  • CD8-Positive T-Lymphocytes (immunology)
  • Cancer Vaccines (genetics, therapeutic use)
  • Cell Line
  • Dendritic Cells (immunology)
  • Female
  • Gangliosides
  • Genetic Vectors
  • Immunotherapy, Adoptive
  • Interferon-gamma (metabolism)
  • Interleukin-15 (genetics, therapeutic use)
  • Interleukins (genetics, therapeutic use)
  • Mice
  • Neuroblastoma (immunology, therapy)
  • T-Lymphocyte Subsets (immunology)

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