The encouraging results obtained from this study performed on a limited number of subjects justify further analysis of the efficacy of the PD-E7/AS02B vaccine in CIN patients.
To elucidate further the potential of a Semliki Forest virus IL-12 genes induced tumor regression, the antiangiogenic-(SFV) vector in vivo for gene therapy, we constructed a activity of SFV-IL12 was investigated using Doppler ultravector, SFV-IL12, to transfer murine IL-12 genes into sonography (DUS). SFV-IL12 inhibited in situ neovascutumors. A single intratumoral injection of established B16 larization within the tumor, without affecting the resistance murine melanoma with SFV-IL12 resulted in a significant index of pre-existing intratumoral blood flows. In addition, inhibition of tumor growth, while injection with SFV-LacZ histological analysis of SFV-IL12-treated tumors showed had no effect. This antitumoral activity correlated with an massive tumor necrosis induced by SFV-IL12 treatment. increase of IFN␥ production, MIG and IP-10 mRNA These data indicate that SFV-IL12 inhibits tumor growth expression, both at the tumor site and at the periphery. In through its antiangiogenic activity, demonstrated for the contrast, no increase in CTL-or NK cell-mediated cytotoxic first time in vivo by DUS, and suggest that the SFV vector response could be detected, ruling out the involvement of may be a novel valuable tool in tumor gene transfer. T and NK cell cytotoxicity. To determine how the transfer of
Human papillomavirus type 16 is commonly implicated in cervical cancers. The viral genome encodes potential targets like the oncoprotein E7, expressed in transformed cells but thought to represent a poorly immunogenic antigen. We describe in this work a DNA-based vaccination protocol aimed at inducing an efficient anti-E7 immune response in vivo. Plasmids allowing the expression of the E7 protein in distinct cellular compartments were generated and assayed in an in vivo model of tumor growth. Our data demonstrate that mice vaccinated with a plasmid encoding for an E7 protein fused to a domain of the MHC class II-associated invariant chain (IiE7) were protected against tumor challenge. Mice immunized against an ubiquitinated form of E7 (Ub(Ala)E7) failed to control tumor growth. Protection induced by IiE7 was correlated with the development of CD8 + CTL and required the presence of CD4 + cells. In vitro studies confirmed that the IiE7 fusion protein was expressed at high levels in the endosomal compartment of transfected cells, while the natural and the ubiquitin-modified form of E7 were mainly nuclear. The present study suggests that an efficient anti-tumor response can be induced in vivo by DNA constructs encoding for E7 protein forms localizing at the endosomal compartment.
The E6 protein of human papillomavirus type 16 (HPV-16), along with E7, is responsible for the HPV-induced malignant transformation of the cervix. However, the mechanism of this transformation activity is not well understood. We investigated whether the entire E6 protein of HPV-16 could act as an activator of transcription. Experiments in which NIH 3T3 cells were cotransfected with an E6 expression vector together with the reporter chloramphenicol acetyltransferase (CAT) gene linked to various minimal promoters indicated that E6 could activate transcription from a series of viral TATA-containing promoters. Mutations or deletions that affected all upstream regulatory elements present in the thymidine kinase (TK) promoter, such as the GC and CAAT boxes, reduced the level of E6-induced transcription. However, compared with the basal level, these truncated promoters were still activated by E6. Although site-directed mutations of the TATA sequence present in the TK or human immunodeficiency virus long terminal repeat promoters reduced the level of basal transcription, they did not abolish the E6-mediated activation. Moreover, E6 could restore almost completely the full level of wild-type E6-induced transcription as long as the upstream regulatory elements (GC/CAAT in the TK promoter, NF-KcB in the human immunodeficiency virus long terminal repeat) were intact. This dual interaction of HPV-16 E6 is reminiscent of the activity of a coactivator.
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