Transfer of the murine interleukin-12 gene in vivo by a Semliki Forest virus vector induces B16 tumor regression through inhibition of tumor blood vessel formation monitored by Doppler ultrasonography

Abstract

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

Regression of mouse tumours and inhibition of metastases following administration of a Semliki Forest virus vector with enhanced expression of IL-12

“…A third antitumour mechanism that may operate is the inhibition of tumour angiogenesis by IL-12, which has been demonstrated in a previous study of tumour treatment by an IL-12-expressing SFV vector. 18 In the present study, the increased levels of the antiangiogenic chemokine IP-10 in the blood of treated mice, allied to the frequent occurrence of thrombosis and haemorrhage in the treated tumours, suggests that inhibition of angiogenesis also played a role in our model system.…”

“…[23][24][25] Previous studies have shown that the amount of IL-12 available at the tumour site is critical for tumour regression, since it determines the number and type of infiltrating leucocytes. 21 It may also mediate the antiangiogenic effect of IL-12, 18 although the relative contribution of these two effects to the antitumour activity of IL-12 is not clear.…”

“…7 SFV vectors expressing the cytokine interleukin-12 (IL-12) induce tumour regression mainly by inhibition of angiogenesis. 18 Clinical trials (Phase I and II) have been planned to use liposomeencapsulated SFV vectors expressing IL-12 in the treatment of several tumours, including glioblastoma multiforme. 19 These and other studies have indicated that the SFV vector is an effective tumour therapy agent.…”

Replication-defective recombinant Semliki Forest virus encoding GM-CSF as a vector system for rapid and facile generation of autologous human tumor cell vaccines

“…38 Direct intratumoral injection of these SFV/IL-12 particles in mice significantly inhibited growth of established B16 melanomas and inhibited neovascularization. 39 Recently, the application of alphavirus replicons has been extended to naked nucleic acids. 40 The relatively high efficacy of self-replicating nucleic acids as compared with DNA vaccines applied in anticancer therapies was correlated with the apoptosis-inducing features of the RNA replicase [41][42][43] and was attributed to mimicking of a viral infection that may trigger danger signals.…”

Induction of apoptosis in BCL‐2‐expressing rat prostate cancer cells using the Semliki Forest virus vector

“…Initially, these were concerned with the stimulation of an anti-tumour immune response 6 -8 or to inhibit angiogenesis through the expression of IL-12. 9 It has also been shown that the induction of p53-independent apoptosis by the SFV vector is an inherent function of the vector RNA and not dependent on expression of cloned heterologous genes. 10 Targeting of alphavirus vectors has been shown to be feasible, although only 1 targeting strategy has so far been described for alphavirus vectors, based on coupling of a monoclonal antibody to a viral spike protein via a protein A sequence.…”