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.