title: Histone H2A-mediated transient cytokine gene delivery induces efficient antitumor responses in murine neuroblastoma.
abstract: A major goal of cancer immunotherapy is the induction of a cell-mediated antitumor response in poorly immunogenic malignancies. We tested the hypothesis that this can be achieved by cytokine gene therapy with a novel histone H2A-based transient transfection procedure. This was tested by using cytokine genes encoding for IL-2 and a single chain IL-12 (scIL-12) fusion protein in a recently developed murine neuroblastoma model. Here, we demonstrate that cytokine gene transfer of IL-2 and scIL-12 with histone H2A results in the induction of an antitumor immune response that is superior in some respects to gene transfer with Superfect, a commercially available activated dendrimer commonly used to effect transfection with plasmids. Three lines of evidence support this contention. First, histone H2A-mediated transfection of IL-2 induces a natural killer cell-induced rejection of primary tumors in contrast to Superfect, which produces only a partial reduction in primary tumor growth. Second, the induction of a T cell-mediated protective tumor immunity following gene transfer of scIL-12 is more efficient with the histone H2A-mediated gene transfer because rejection of a lethal wild-type tumor cell challenge is accompanied by the greatest degree of MHC class I-restricted tumor cell killing in vitro. Third, histone H2A-mediated scIL-12 gene therapy induces the greatest release of mIFN-gamma from splenocytes of vaccinated animals in contrast to Superfect and other controls.
authors.affiliation: Departments of Molecular and Experimental Medicine and Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: D
authors.initials: D
authors.lastname: Balicki
authors.forename: R A
authors.initials: RA
authors.lastname: Reisfeld
authors.forename: U
authors.initials: U
authors.lastname: Pertl
authors.forename: E
authors.initials: E
authors.lastname: Beutler
authors.forename: H N
authors.initials: HN
authors.lastname: Lode
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy; D006657:Histones / Q000235:genetics*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics*; D051379:Mice; D009447:Neuroblastoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D006657:Histones; D007376:Interleukin-2; D007371:Interferon-gamma