Histone H2A-mediated transient cytokine gene delivery induces efficient antitumor responses in murine neuroblastoma

A major goal of cancer immunotherapy is the induction of a cell-mediated an titumor response in poorly immunogenic malignancies. We tested the hypothes is that this can be achieved by cytokine gene therapy with a novel histone H2A-based transient transfection procedure. This was tested by using cytoki ne genes encoding for IL-2 and a single chain IL-12 (scIL-12) fusion protei n 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 res pects to gene transfer with Superfect, a commercially available activated d endrimer 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 primar y tumor growth. Second, the induction of a T cell-mediated protective tumor immunity following gene transfer of scIL-12 is more efficient with the his tone H2A-mediated gene transfer because rejection of a lethal wild-type tum or cell challenge is accompanied by the greatest degree of MHC class I-rest ricted tumor cell killing in vitro. Third, histone H2A-mediated scIL-12 gen e therapy induces the greatest release of mIFN-gamma from splenocytes of va ccinated animals in contrast to Superfect and other controls.