The Semliki Forest virus vector induces p53-independent apoptosis.

Glasgow, Gwendoline M.; McGee, Margaret M.; Tarbatt, Catherine J.; Mooney, Dorothy A.; Sheahan, B. J.; Atkins, Gregory J.

doi:10.1099/0022-1317-79-10-2405

Cited by 74 publications

(82 citation statements)

References 26 publications

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“…SFV vectors have an inherent p53-independent apoptosis inducing capability, 6 which has been successfully used to treat tumours in nude mice, 7,37 and it is likely that this operates also for the vectors used in this study. However, the presence of the enhancer in rSFV10-E-IL12 is unlikely to increase this inherent apoptosis induction since all cells infected by the unenhanced vector undergo apoptosis and the vector does not spread intercellularly.…”

Section: Discussionmentioning

confidence: 99%

“…However, the presence of the enhancer in rSFV10-E-IL12 is unlikely to increase this inherent apoptosis induction since all cells infected by the unenhanced vector undergo apoptosis and the vector does not spread intercellularly. 6,7,37 The enhanced ability of this vector to destroy tumour cells must therefore result from the induction of enhanced IL-12 secretion. IL-12 has a potent proinflammatory activity that may contribute to the antitumour effect.…”

Section: Discussionmentioning

confidence: 99%

“…Alphavirus vectors demonstrate high-level expression of heterologous proteins in a broad host range of cells [1][2][3][4][5] and have been shown to induce apoptosis in infected cells. 6,7 Semliki Forest virus (SFV), an alphavirus, is an enveloped positive-sense RNA virus of the family Togaviridae; it has been developed into a transient RNA-based suicidal expression vector system. 8 This system consists of a vector in which foreign genes can be expressed, and two helper vectors that encode the structural protein genes.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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The Semliki Forest virus (SFV) vector is an RNA-based suicide expression vector that has been used experimentally for tumour therapy. Recently, a new enhanced vector pSFV10-E has been developed that expresses foreign genes at levels up to 10 times higher than the original vector. Interleukin-12 (IL-12), an immunomodulatory cytokine, plays a key role in the induction of T-helper1 responses. The two IL-12 gene subunits were cloned from mouse splenocytes and inserted into the pSFV10-E and pSFV10 (nonenhanced) vectors. Both constructs expressed and secreted biologically active murine IL-12. Administration of high titre rSFV10-E-IL12 particles intratumourally to treat implanted K-BALB tumours in BALB/c mice demonstrated complete tumour regression in comparison to control or rSFV10-IL12 treated groups. High titre rSFV10-E-IL12 particles were also effective in the CT26 tumour model. Histological and immunohistochemical studies revealed tumour necrosis in addition to aggressive influx of CD4+ and CD8+ T cells and other immune cells. Furthermore, inhibition of primary tumour growth and lung metastases of a metastatic (4T1) tumour model indicated the potential of high titres of rSFV10-E-IL12 particles as an efficient antitumour therapeutic agent.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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“…Infection of cells does not proceed beyond a single round and the infected cells die by apoptosis. 29 The transient nature of infection with recombinant SFV thus provides an important safety advantage when considering using SFV as a vaccine in humans.…”

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Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Riezebos‐Brilman

Regts

et al. 2005

Gene Ther

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Despite promising preclinical results of various therapeutic anticancer immunization strategies, these approaches may not be effective enough to eradicate tumors in cancer patients. While most animal models are based on fastgrowing transplantable tumors, malignancies in, for example, cervical cancer patients in general develop much more slowly, which may lead to immune suppression and/or immune tolerance. As a consequence, the immunomodulating signal of any therapeutic immunization regimen should be sufficiently potent to overcome this immunocompromised condition. In previous studies, we demonstrated that an experimental vaccine against human papillomavirus (HPV)-induced cervical cancer, based on Semliki Forest virus (SFV), induces robust HPV-specific cellular immune responses in mice. Now we studied whether this strategy is potent enough to also prime a cellular immune response in immune-tolerant HPV transgenic mice, in which CTL activity cannot be induced using protein or DNA vaccines. We demonstrate that, depending on the route of immunization, SFV-expressing HPV16 E6 and E7 indeed has the capacity to induce HPV16 E7-specific cytotoxic T cells in HPVtransgenic mice. Gene Therapy (2005) Cervical cancer is the third most common cancer among women worldwide. It is caused by infection with highrisk human papillomavirus (HPV), in particular types 16, 18, 31, 33 or 45. Indeed, in over 99% of all cervical carcinomas, DNA derived from these HPV types is detectable. 1 High-risk HPVs have the capacity to transform cervical epithelial cells by integrating the open reading frames encoding the viral early proteins E6 and E7 into the host cell genome. This integration may lead to constitutive overexpression of E6 and E7, mediating transformation of the cells to a malignant phenotype. 2 Since the continued production of E6 and E7 is required for the maintenance of the transformed phenotype, E6 and E7 in fact represent tumor-specific antigens in cervical carcinoma and premalignant HPV-transformed cells. As a consequence, E6 and E7 are potential targets for immunotherapeutic intervention strategies involving induction or stimulation of cytotoxic T lymphocyte (CTL) activity against HPV-transformed cells. 3

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“…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. 11 Other targeting strategies involving modification of the viral spike proteins may be feasible, as has been described for adenovirus vectors.…”

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confidence: 99%

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

2001

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The Semliki Forest virus (SFV) vector is a transient RNA expression vector that has an inherent p53-independent apoptosis-inducing property. It is administered as recombinant SFV particles (rSFV) that undergo 1 round of replication only and express a gene cloned into the multicloning site. In our study we have investigated the ability of the SFV vector to induce apoptosis and inhibit tumour growth in rat prostate cancer (AT3-Neo) cells expressing the Bcl-2 oncogene (AT3-Bcl-2 cells), which normally inhibits apoptosis. rSFV expressing the enhanced green fluorescent protein (EGFP) gene (rSFV-EGFP), or recombinant RNA transfected into cells by electroporation, induced delayed apoptosis in AT3-Bcl-2 cells. SFV-mediated expression of a cloned pro-apoptotic Bax gene by the vector, however, enhanced apoptosis induction both in AT3-Bcl-2 cells and standard BHK-21 cells. Such Bax-expressing particles could be produced only at low titers compared to EGFP-expressing particles under standard conditions for particle production, but lowering the incubation temperature for particle production to 33°C partially alleviated this effect. Bax-expressing particles were shown to inhibit the growth of AT3-Neo and AT3-Bcl-2 tumours in nude mice, as did high titre EGFP-expressing particles. It is concluded that SFV recombinant particles have potential as antitumour agents to treat apoptosis-resistant tumours.

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The Semliki Forest virus vector induces p53-independent apoptosis.

Cited by 74 publications

References 26 publications

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

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

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

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

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