title: Immunotherapy with a posttranscriptionally modified DNA vaccine induces complete protection against metastatic neuroblastoma.
abstract: The successful induction of a T-cell-mediated tumor-protective immunity against poorly immunogenic malignancies remains a major challenge for cancer immunotherapy. We achieved this by immunization with a tyrosine hydroxylase (mTH)-based DNA vaccine, enhanced with the posttranscriptional regulatory acting RNA element (WPRE), derived from woodchuck hepatitis virus in combination with an antibody-cytokine fusion protein (ch14.18-IL-2) that targets interleukin-2 (IL-2) to the tumor microenvironment. This DNA vaccine mTH-WPRE was carried by attenuated Salmonella typhimurium and applied by oral gavage in a mouse model of neuroblastoma. Mice immunized with the mTH-WPRE vaccine, and which additionally received a boost with suboptimal doses of ch14.18-IL-2, were completely protected against hepatic neuroblastoma metastases. In contrast, all controls presented with disseminated metastases. Both T-cell and natural killer (NK) cell-dependent mechanisms were involved in the induction of a systemic tumor-protective immunity. Thus, up-regulation of interferon-gamma (IFN-gamma) expression in CD8(+) T cells occurred only in those animals that received the mTH-WPRE vaccine plus the ch14.18-IL-2 boost. Up-regulation of this proinflammatory cytokine was not observed in mice immunized with mTH-WPRE vaccine alone. A role for NK cells was indicated by the complete abrogation of systemic tumor-protective immunity in all animals that were depleted of NK cells in vivo. Taken together, these data demonstrate that immunization with a posttranscriptionally enhanced DNA vaccine encoding the WPRE sequence, combined with a boost of the ch14.18-IL-2 fusion protein, completely protects against hepatic metastases in a murine model of neuroblastoma and therefore may lead to a new strategy for immunotherapy and prevention of metastatic neuroblastoma.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Ursula
authors.initials: U
authors.lastname: Pertl
authors.forename: Harald
authors.initials: H
authors.lastname: Wodrich
authors.forename: J Michael
authors.initials: JM
authors.lastname: Ruehlmann
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Gillies
authors.forename: Holger N
authors.initials: HN
authors.lastname: Lode
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Reisfeld
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D009362:Neoplasm Metastasis / Q000517:prevention & control / Q000628:therapy; D009447:Neuroblastoma / Q000473:pathology / Q000628:therapy*; D012323:RNA Processing, Post-Transcriptional; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome; D014446:Tyrosine 3-Monooxygenase; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*
chemical_list: D019496:Cancer Vaccines; D007376:Interleukin-2; D019444:Vaccines, DNA; D014446:Tyrosine 3-Monooxygenase