Semliki Forest Virus Expressing Interleukin-12 Induces Antiviral and Antitumoral Responses in Woodchucks with Chronic Viral Hepatitis and Hepatocellular Carcinoma

Rodríguez-Madoz, Juan R.; Liu, Katherine H.; Quetglas, José I.; Ruiz-Guillen, Marta; Otano, Itziar; Crettaz, Julien; Butler, Scott D.; Bellezza, Christine A.; Dykes, Nathan L.; Tennant, Bud C.; Prieto, Jesús; González‐Aseguinolaza, Gloria; Smerdou, Cristian; Menne, Stephan

doi:10.1128/jvi.01597-09

Cited by 43 publications

(44 citation statements)

References 53 publications

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“…These propagation-deficient vectors can accommodate expression cassettes and have been engineered to encode cytokines and other proimmunogenic transgenes. A SFV vector encoding the heterodimeric murine interleukin-12 (IL12; SFV-IL12) proteins (3)(4)(5) under the control of two independent subgenomic promoters is a powerful antitumor agent when directly injected into experimental tumors (6). The effect is the result of killing tumor cells in an immunogenic fashion, the local effects of the IL12 transgene, and the innate immune activation caused by viral RNA, including a powerful type I IFN response (7).…”

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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“…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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“…38 This virus-induced type I IFN response can synergize with other cytokines or tumor antigens expressed from the SFV vector, resulting in good antitumor responses. 27,28,41 However, we have shown that overexpression of IFNa from SFV in the absence of other therapeutic transgenes is non-redundant and, moreover, essential to achieve a therapeutic antitumor activity. These results were supported by the fact that co-injection of SFV-LacZ with rIFNa was able to induce a similar level of antitumor activity than SFV-IFN.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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Semliki Forest virus (SFV) represents a promising gene therapy vector for tumor treatment, because it produces high levels of recombinant therapeutic proteins while inducing apoptosis in infected cells. In this study, we constructed a SFV vector expressing murine interferon alpha (IFNa). IFNa displays antitumor activity mainly by enhancing an antitumor immune response, as well as by a direct antiproliferative effect. In spite of the antiviral activity of IFNa, SFV-IFN could be produced in BHK cells at high titers. This vector was able to infect TC-1 cells, a tumor cell line expressing E6 and E7 proteins of human papillomavirus, leading to high production of IFNa both in vitro and in vivo. When injected into subcutaneous TC-1 tumors implanted in mice, SFV-IFN was able to induce an E7-specific cytotoxic T lymphocyte response, and to modify tumor infiltrating immune cells, reducing the percentage of T regulatory cells and activating myeloid cells. As a consequence, SFV-IFN was able to eradicate 58% of established tumors treated 21 days after implantation with long-term tumor-free survival and very low toxicity. SFV-IFN was also able to induce significant antitumor responses in a subcutaneous tumor model of murine colon adenocarcimoma. These data suggest that local production of IFNa by intratumoral injection of recombinant SFV-IFN could represent a potent new strategy to treat tumors in patients.

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Semliki Forest Virus Expressing Interleukin-12 Induces Antiviral and Antitumoral Responses in Woodchucks with Chronic Viral Hepatitis and Hepatocellular Carcinoma

Cited by 43 publications

References 53 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 Semliki Forest virus vector engineered to express IFNα induces efficient elimination of established tumors

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