Increased Efficacy and Safety in the Treatment of Experimental Liver Cancer with a Novel Adenovirus-Alphavirus Hybrid Vector

Guan, Mingyu; Rodríguez-Madoz, Juan R.; Alzuguren, Pilar; Gomar, Celia; Kramer, M. Gabriela; Kochanek, Stefan; Prieto, Jesús; Smerdou, Cristian; Qian, Cheng

doi:10.1158/0008-5472.can-05-0877

Cited by 32 publications

(31 citation statements)

References 40 publications

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“…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). 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based on a viral-positive single stranded (ss)RNA genome, in which the region coding for the structural proteins has been replaced by the transgene (19).…”

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based on a viral-positive single stranded (ss)RNA genome, in which the region coding for the structural proteins has been replaced by the transgene (19).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%

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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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Section: Introductionmentioning

confidence: 99%

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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“…In an attempt to develop a system that can also be applied to liver cancer, we searched for a liver cancerspecific promoter and identified several potential liver cancer-specific promoter candidates, including a-fetoprotein (AFP) basic promoter and AFP basic promoter combined with AFP enhancers (eAFP), both of which have already been known for being highly liver cancer specific (Kim and Wang, 2003;Lu et al, 2003;Shi et al, 2004;Suriawinata and Xu, 2004;Lemken et al, 2005;Guan et al, 2006). AFP, produced by the yolk sac and liver, is expressed at high levels during early development in fetus and decreases to a low or undetected level in adults (Abelev and Eraiser, 1999).…”

Section: Introductionmentioning

confidence: 99%

Targeted hepatocellular carcinoma proapoptotic BikDD gene therapy

Dai

Yeh

et al. 2010

Oncogene

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“…No systemic or liver toxicities were observed. Our data suggest that this new type of adenovirus-alphavirus hybrid vector may provide a potent and safe tool for cancer gene therapy [27].…”

Section: Hybrid Vector For Gene Therapy Of Cancermentioning

confidence: 78%

Therapy of cancer by cytokines mediated by gene therapy approach

2006

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Gene therapy offers a new approach for treatment of cancer. Transfer of genes encoding immunostimulatory cytokines has been used with remarkable success to eliminate cancer in animals. However, clinical trials in patients with this strategy had limited efficacy. Therefore, improvement of gene transfer vector system is necessary. A hybrid viral vector, consisting of SFV replicon with either murine IL-12 or reporter LacZ gene, was constructed. This hybrid vector showed specificity and high level of expression in HCC both in vitro and in vivo. In a rat orthotropic liver tumor model, treatment of established tumors by the hybrid vector with mIL-12 gene resulted in a strong anti-tumor activity without accompanying toxicity. Subsequently, a helper-dependent adenovirus vectors containing a mifepristone (RU486) inducible system was constructed for controlled and liver-specific expression of human interleukin 12 (hIL-12) (HD-Ad/RUhIL-12) and mouse IL-12 (mIL-12) (HD-Ad/RUmIL-12). Data showed that high and sustained serum levels of hIL-12 could be attained by continuing administration of RU486 every 12 or 24 h. Repetitive induction of hIL-12 could be obtained over, at least, a period of 48 weeks after a single injection of HD-Ad/RUhIL-12. Treatment of liver metastases with of HD-Ad/RUmIL-12 plus RU846 resulted in complete tumor regression in all animals. Then, different cytokine genes were inserted into conditional replicative adenoviruses vectors (also called oncolytic adenovirus). Replication of adenovirus in tumor cells would kill tumor cells and release viruses, which infect surrounding tumor cells. The combination of cytopathic effect by oncolytic adenovirus and biological effect of transgene would exert strong antitumor activity. These new types of vectors may provide a potent and safe tool for cancer gene therapy.

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Increased Efficacy and Safety in the Treatment of Experimental Liver Cancer with a Novel Adenovirus-Alphavirus Hybrid Vector

Cited by 32 publications

References 40 publications

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

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

Targeted hepatocellular carcinoma proapoptotic BikDD gene therapy

Therapy of cancer by cytokines mediated by gene therapy approach

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