title: CpG oligonucleotides enhance the tumor antigen-specific immune response of a granulocyte macrophage colony-stimulating factor-based vaccine strategy in neuroblastoma.
abstract: Granulocyte macrophage colony-stimulating factor (GM-CSF)-transduced autologous tumor cells form the basis of many immunotherapeutic strategies. We tested whether combining this approach with T-helper 1 (Th-1)-like immunostimulatory CpG oligodeoxynucleotides (CpG ODNs) would improve therapeutic efficacy in an established model of murine neuroblastoma. The weakly immunogenic Neuro-2a cell line was used in syngeneic A/J mice. CpG 1826 was tested for its antitumor effect alone and as an adjuvant to Neuro-2a cells retrovirally transduced to express murine GM-CSF (GM/Neuro-2a). Three days after wild-type (WT) tumor cell inoculation, mice in different groups were s.c. vaccinated in the opposite leg with combinations of WT neuro2a, irradiated (15 Gy) WT or GM/Neuro-2a transfectants with or without CpG 1826 (200 micro g). To test for the induction of memory responses, mice that rejected their tumor were rechallenged with WT Neuro-2a (1 x 10(6)) 7 weeks after vaccination. All of the mice in the control (unvaccinated) group died within 3 weeks after Neuro-2a inoculation. Most of the vaccinated groups had only minimal-to-modest antitumor responses, and the mice succumbed to tumor. Tumor growth was remarkably inhibited in the group of mice that received irradiated GM/Neuro-2a plus CpG and four (50%) of eight mice in this group survived tumor free. Tumor-free mice were resistant to further WT tumor cell challenge, indicating a memory response. Mechanistic studies showed that CpG alone induced a favorable Th-1-like cytokine immune response and vaccine-induced tumor cell killing was dependent on both CD4 and CD8 T cells that killed tumor cell targets by apoptosis. These results demonstrate that CpG ODNs enhanced the antitumor effect of irradiated GM-CSF secreting Neuro-2a cells. This vaccine strategy elicits a potent tumor antigen-specific immune response against established murine neuroblastoma and generates systemic neuroblastoma-specific immunity.
authors.affiliation: Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa 52246, USA.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Sandler
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Chihara
authors.forename: Gen
authors.initials: G
authors.lastname: Kobayashi
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhu
authors.forename: Michal A
authors.initials: MA
authors.lastname: Miller
authors.forename: David L
authors.initials: DL
authors.lastname: Scott
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Krieg
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D018899:CpG Islands / Q000235:genetics; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016233:Immunotherapy, Active / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D009447:Neuroblastoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D009841:Oligonucleotides / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D018417:Th1 Cells / Q000276:immunology; D014162:Transfection
chemical_list: D017252:CD3 Complex; D019496:Cancer Vaccines; D009841:Oligonucleotides; D016178:Granulocyte-Macrophage Colony-Stimulating Factor