Alphavirus vectors for cancer therapy

Quetglas, José I.; Ruiz-Guillen, Marta; Aranda, Alejandro; Casales, Erkuden; Bezunartea, Jaione; Smerdou, Cristian

doi:10.1016/j.virusres.2010.07.027

Cited by 59 publications

(54 citation statements)

References 168 publications

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“…Semliki Forest virus (SFV)-based RNA viral vectors have been developed for vaccination and immunotherapy of cancer (1,2). These propagation-deficient vectors can accommodate expression cassettes and have been engineered to encode cytokines and other proimmunogenic transgenes.…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…Several viral vectors, such as adenovirus, retrovirus, or alphavirus, have been used to deliver IL12 to the tumor site in different animal tumor models (14)(15)(16). Replication-defective alphavirus vectors based on Semliki Forest virus (SFV) have shown several advantages over adenoviral vectors in preclinical studies of cancer treatment, such as higher expression levels, and induction of immunogenic apoptosis in the infected tumor cells, in which abundant viral RNA co-opts all the protein translation machinery (17,18).…”

Section: Introductionmentioning

confidence: 99%

“…SFV vectors are based on a viral-positive single stranded (ss)RNA genome, in which the region coding for the structural proteins has been replaced by the transgene (19). SFV vectors expressing IL12 (SFV-IL12) have been shown to be very efficient in inducing therapeutic antitumor responses mediated by antitumor cytotoxic T lymphocytes in tumor models of colon adenocarcinoma, sarcoma, and glioma in mice (16), orthotopic hepatocellular carcinoma in rats (18), and spontaneous hepatocellular carcinoma in woodchucks (20).…”

Section: Introductionmentioning

confidence: 99%

Strict Requirement for Vector-Induced Type I Interferon in Efficacious Antitumor Responses to Virally Encoded IL12

et al. 2015

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Host responses are increasingly considered important for the efficacious response to experimental cancer therapies that employ viral vectors, but little is known about the specific nature of host responses required. In this study, we investigated the role of host type I interferons (IFN-I) in the efficacy of virally delivered therapeutic genes. Specifically, we used a Semliki Forest virus encoding IL12 (SFV-IL12) based on its promise as an RNA viral vector for cancer treatment. Intratumoral injection of SFV-IL12 induced production of IFN-I as detected in serum. IFN-I production was abolished in mice deficient for the IFNβ transcriptional regulator IPS-1 and partially attenuated in mice deficient for the IFNβ signaling protein TRIF. Use of bone marrow chimeric hosts established that both hematopoietic and stromal cells were involved in IFN-I production. Macrophages, plasmacytoid, and conventional dendritic cells were each implicated based on cell depletion experiments. Further, mice deficient in the IFN-I receptor (IFNAR) abolished the therapeutic activity of SFV-IL12, as did a specific antibody-mediated blockade of IFNAR signaling. Reduced efficacy was not caused by an impairment in IL12 expression, because IFNAR-deficient mice expressed the viral IL12 transgene even more strongly than wild-type (WT) hosts. Chimeric host analysis for the IFNAR involvement established a strict requirement in hematopoietic cells. Notably, although tumor-specific CD8 T lymphocytes expanded robustly after intratumoral injection of WT mice with SFV-IL12, this did not occur in mice where IFNAR was inactivated genetically or pharmacologically. Overall, our results argued that the antitumor efficacy of a virally based transgene therapeutic relied strongly on a vector-induced IFN-I response, revealing an unexpected mechanism of action that is relevant to a broad array of current translational products in cancer research. Cancer Res; 75(3); 497–507. ©2014 AACR.

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“…These SFV replicons could be packaged into viral particles by providing helper RNAs expressing SFV capsid and envelope proteins in trans [36], or by expressing these proteins from inducible promoters in the same cells. Since cytopathic alphavirus vectors have shown a great potential for vaccination and cancer gene therapy, the cell lines described in this work could also be attractive for this field [37].…”

Section: Discussionmentioning

confidence: 99%

A quick and efficient method to generate mammalian stable cell lines based on a novel inducible alphavirus DNA/RNA layered system

Aranda

Bezunartea²,

Casales

et al. 2014

Cell. Mol. Life Sci.

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proteins contained posttranslational modifications, showed bioactivity, and were efficiently purified. Remarkably, this system allowed production of toxic proteins, like oncostatin-M, since cells able to express it could be grown to the desired amount before induction. These cell lines were easily adapted to growth in suspension, making this methodology very attractive for therapeutic protein production.

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Alphavirus vectors for cancer therapy

Cited by 59 publications

References 168 publications

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

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

Strict Requirement for Vector-Induced Type I Interferon in Efficacious Antitumor Responses to Virally Encoded IL12

A quick and efficient method to generate mammalian stable cell lines based on a novel inducible alphavirus DNA/RNA layered system

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