A Semliki Forest virus vector engineered to express IFNα induces efficient elimination of established tumors

Quetglas, José I.; Fioravanti, Jessica; Ardaiz, Nuria; Medina-Echeverz, José; Baraibar, Iosune; Prieto, Jesús; Smerdou, Cristian; Berraondo, Pedro

doi:10.1038/gt.2011.99

Cited by 20 publications

(15 citation statements)

References 47 publications

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“…Plasmids pSFV-enhLacZ, pSFV-Luc, and pSFV-enhIL-12 have been described previously. 10,42 RNA synthesis from SFV plasmids, transfection into BHK-21 cells by electroporation, and packaging of recombinant RNA into SFV vp were performed as described previously. 36 Briefly, BHK-21 cells were co-electroporated with the recombinant RNA, together with two helper RNAs (i.e., SFV-helper-C-S219A and SFV-helper-S2 RNAs), which provided in trans the capsid and the spike proteins, respectively.…”

Section: Methodsmentioning

confidence: 99%

Immunotherapeutic Synergy Between Anti-CD137 mAb and Intratumoral Administration of a Cytopathic Semliki Forest Virus Encoding IL-12

et al. 2012

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Intratumoral injection of Semliki Forest virus encoding interleukin-12 (SFV-IL-12) combines acute expression of IL-12 and stressful apoptosis of infected malignant cells. Agonist antibodies directed to costimulatory receptor CD137 (4-1BB) strongly amplify pre-existing cellular immune responses toward weak tumor antigens. In this study, we provide evidence for powerful synergistic effects of a combined strategy consisting of intratumoral injection of SFV-IL-12 and systemic delivery of agonist anti-CD137 monoclonal antibodies (mAbs), which was substantiated against poorly immunogenic B16 melanomas (B16-OVA and B16.F10) and TC-1 lung carcinomas. Effector CD8 + T cells were sufficient to mediate complete tumor eradications. Accordingly, there was an intensely synergistic in vivo enhancement of cytotoxic T lymphocytes (CTL)-mediated immunity against the tumor antigens OVA and tyrosine-related protein-2 (TRP-2). This train of phenomena led to long-lasting tumor-specific immunity against rechallenge, attained transient control of the progression of concomitant tumor lesions that were not directly treated with SFV-IL-12 and caused autoimmune vitiligo. Importantly, we found that SFV-IL-12 intratumoral injection induces bright expression of CD137 on most tumor-infiltrating CD8 + T lymphocytes, thereby providing more abundant targets for the action of the agonist antibody. This efficacious combinatorial immunotherapy strategy offers feasibility for clinical translation since anti-CD137 mAbs are already undergoing clinical trials and development of clinical-grade SFV-IL-12 vectors is in progress.

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Section: Methodsmentioning

confidence: 99%

Immunotherapeutic Synergy Between Anti-CD137 mAb and Intratumoral Administration of a Cytopathic Semliki Forest Virus Encoding IL-12

et al. 2012

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“…Plasmids pSFV-enhLacZ and pSFV-enhIL12 have been described previously (4,15). Plasmid pSFV-NS3 encodes the cytoplasmic Hepatitis C virus NS3 protein (C. Smerdou and colleagues; unpublished results).…”

Section: Vector Productionmentioning

confidence: 99%

Virotherapy with a Semliki Forest Virus–Based Vector Encoding IL12 Synergizes with PD-1/PD-L1 Blockade

Quetglas

Labiano

Aznar

et al. 2015

Cancer Immunology Research

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Virotherapy and checkpoint inhibitors can be combined for the treatment of cancer with complementarity and potential for synergistic effects. We have developed a cytolytic but nonreplicative viral vector system based on Semliki Forest virus that encodes IL12 (SFV-IL12). Following direct intratumoral injection, infected cells release transgenic IL12, die, and elicit an inflammatory response triggered by both abundantly copied viral RNA and IL12. In difficult-to-treat mouse cancer models, such as those derived from MC38 and bilateral B16-OVA, SFV-IL12 synergized with an anti-PD-1 monoclonal antibody (mAb) to induce tumor regression and prolong survival. Similar synergistic effects were attained upon PD-L1 blockade. Combined SFV-IL12 þ anti-PD-1 mAb treatment only marginally increased the elicited cytotoxic T-lymphocyte response over SFV-IL12 as a single agent, at least when measured by in vivo killing assays. In contrast, we observed that SFV-IL12 treatment induced expression of PD-L1 on tumor cells in an IFNgdependent fashion. PD-L1-mediated adaptive resistance thereby provides a mechanistic explanation of the observed synergistic effects achieved by the SFV-IL12 þ anti-PD-1 mAb combination.

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“…Plasmids pSFV-enhIL-12 and pSFV-enhLacZ, containing genes coding for mouse IL-12 and b-galactosidase, respectively, were described previously (17,20). Vector RNA synthesis and transfection into BHK-21 cells by electroporation was performed as described previously (16).…”

Section: Plasmids and Vector Productionmentioning

confidence: 99%

Eradication of Liver-Implanted Tumors by Semliki Forest Virus Expressing IL-12 Requires Efficient Long-Term Immune Responses

Quetglas

Rodríguez-Madoz

Bezunartea

et al. 2013

The Journal of Immunology

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Semliki Forest virus vectors expressing IL-12 (SFV–IL-12) were shown to induce potent antitumor responses against s.c. MC38 colon adenocarcinomas in immunocompetent mice. However, when MC38 tumors were implanted in liver, where colon tumors usually metastasize, SFV–IL-12 efficacy was significantly reduced. We reasoned that characterization of immune responses against intrahepatic tumors in responder and nonresponder animals could provide useful information for designing more potent antitumor strategies. Remarkably, SFV–IL-12 induced a high percentage of circulating tumor-specific CD8 T cells in all treated animals. Depletion studies showed that these cells were essential for SFV–IL-12 antitumor activity. However, in comparison with nonresponders, tumor-specific cells from responder mice acquired an effector-like phenotype significantly earlier, were recruited more efficiently to the liver, and, importantly, persisted for a longer period of time. All treated mice had high levels of functional specific CD8 T cells at 8 d posttreatment reflected by both in vivo killing and IFN-γ–production assays, but responder animals showed a more avid and persistent IFN-γ response. Interestingly, differences in immune responses between responders and nonresponders seemed to correlate with the immune status of the animals before treatment and were not due to the treatment itself. Mice that rejected tumors were protected against tumor rechallenge, indicating that sustained memory responses are required for an efficacious therapy. Interestingly, tumor-specific CD8 T cells of responder animals showed upregulation of IL-15Rα expression compared with nonresponders. These results suggest that SFV–IL-12 therapy could benefit from the use of strategies that could either upregulate IL-15Rα expression or activate this receptor.

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A Semliki Forest virus vector engineered to express IFNα induces efficient elimination of established tumors

Cited by 20 publications

References 47 publications

Immunotherapeutic Synergy Between Anti-CD137 mAb and Intratumoral Administration of a Cytopathic Semliki Forest Virus Encoding IL-12

Immunotherapeutic Synergy Between Anti-CD137 mAb and Intratumoral Administration of a Cytopathic Semliki Forest Virus Encoding IL-12

Virotherapy with a Semliki Forest Virus–Based Vector Encoding IL12 Synergizes with PD-1/PD-L1 Blockade

Eradication of Liver-Implanted Tumors by Semliki Forest Virus Expressing IL-12 Requires Efficient Long-Term Immune Responses

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