Induction of Tumor Antigen-Specific Immunity In Vivo by a Novel Vaccinia Vector Encoding Safety-Modified Simian Virus 40 T Antigen

摘要: Recent developments support the hypothesis that simian virus 40 (SV40) T antigen (Tag) is a relevant target for immunotherapy human cancers. Contemporary assays DNA sequences have found SV40 in majority of osteosarcomas, bone tumors, ependymomas, choroid plexus and mesotheliomas been evaluated (1-5). Expression Tag protein brain tumors has demonstrated, functional studies (6,7) shown can interfere with functions p53 retinoblastoma mesotheliomas. The possible relationship between polio vaccines contaminated SV40, which were administered to more than 98 million subjects from 1955 through early 1963, oncogenesis these cancers remains controversial (8). Nonetheless, subsequently increasing occurrence mesothelioma, lethal cancer commonly expresses limited treatment options, disconcerting (9). Strategies targeting represent rational avenue developing new therapies such Tag-expressing cancers. SV40 several attributes make it potentially useful recombinant vaccine strategies. First, because genuine tumor-associated not present normal host cells, this need overcome tolerance achieve efficacy circumvent potential hazard autoimmune responses against antigens coexpressed by tumor tissue. Second, apart its association certain cancers, also pathogenic rodent models, providing unique setting optimizing clinically animal models (10). Third, immunogenicity studied extensively (11-13), insight approaches development therapeutic strategies antigen. Despite Tag, strategy safe effective therapy pre-established previously elusive. To determine whether poxvirus would provide an unprecedented established we made novel vaccinia construct. This vector encodes safety-modified sequence (mTag) excludes binding site, amino-terminal oncogenic CR1 J domains optimize clinical safety but preserves immunogenic domains. After confirming expression expected fragment construct termed vaccinia-encoding mTag (vac-mTag), undertaken evaluate vivo. These evidence vac-mTag efficiently prime immune response antigen-specific protection tumors.