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.
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.
Kowalczyk
Aleksandra
A
Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. danuta.kozbor@roswellpark.org
Wierzbicki
Andrzej
A
Gil
Margaret
M
Bambach
Barbara
B
Kaneko
Yutaro
Y
Rokita
Hanna
H
Repasky
Elizabeth
E
Fenstermaker
Robert
R
Brecher
Martin
M
Ciesielski
Michael
M
Kozbor
Danuta
D
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000627:therapeutic use*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005732:Gangliosides; D005822:Genetic Vectors; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics / Q000627:therapeutic use*; D007378:Interleukins / Q000235:genetics / Q000627:therapeutic use*; D051379:Mice; D009447:Neuroblastoma / Q000276:immunology / Q000628:therapy*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D000098546:Interleukin-21
D019496:Cancer Vaccines; D005732:Gangliosides; D019409:Interleukin-15; D007378:Interleukins; C019403:ganglioside, GD2; D007371:Interferon-gamma; D000098546:Interleukin-21