Type I Interferon-Sensitive Recombinant Newcastle Disease Virus for Oncolytic Virotherapy

Elankumaran, Subbiah; Chavan, Vrushali; Qiao, Dan; Raghunath, Shobana; Moorkanat, Gopakumar; Biswas, Moanaro; Samal, Siba K.

doi:10.1128/jvi.01553-09

Cited by 74 publications

(65 citation statements)

References 44 publications

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“…The interferon status of tumor cells has also been proven highly influential on the oncolytic activities of several viruses, IAV included (53,73,74). A recent publication detailing the susceptibility of PDA cell lines to vesicular stomatitis virus found that the lack of type I interferon (IFN) production by AsPC-1, CFPAC-1, MIA PaCa-2, and Panc-1 cells largely correlated with sensitivity to infection; however, both IFN-negative BxPC-3 cells and IFN-producing HPDE6 cells showed resistance (75).…”

Section: Discussionmentioning

confidence: 99%

Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

Kasloff

Pizzuto

Silic-Benussi

et al. 2014

J Virol

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Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of human cancer, with dismal survival rates due to late-stage diagnoses and a lack of efficacious therapies. Building on the observation that avian influenza A viruses (IAVs) have a tropism for the pancreas in vivo, the present study was aimed at testing the efficacy of IAVs as oncolytic agents for killing human PDA cell lines. Receptor characterization confirmed that human PDA cell lines express the alpha-2,3-and the alpha-2,6-linked glycan receptor for avian and human IAVs, respectively. PDA cell lines were sensitive to infection by human and avian IAV isolates, which is consistent with this finding. Growth kinetic experiments showed preferential virus replication in PDA cells over that in a nontransformed pancreatic ductal cell line. Finally, at early time points posttreatment, infection with IAVs caused higher levels of apoptosis in PDA cells than gemcitabine and cisplatin, which are the cornerstone of current therapies for PDA. In the BxPC-3 PDA cell line, apoptosis resulted from the engagement of the intrinsic mitochondrial pathway. Importantly, IAVs did not induce apoptosis in nontransformed pancreatic ductal HPDE6 cells. Using a model based on the growth of a PDA cell line as a xenograft in SCID mice, we also show that a slightly pathogenic avian IAV significantly inhibited tumor growth following intratumoral injection. Taken together, these results are the first to suggest that IAVs may hold promise as future agents of oncolytic virotherapy against pancreatic ductal adenocarcinomas. IMPORTANCEDespite intensive studies aimed at designing new therapeutic approaches, PDA still retains the most dismal prognosis among human cancers. In the present study, we provide the first evidence indicating that avian IAVs of low pathogenicity display a tropism for human PDA cells, resulting in viral RNA replication and a potent induction of apoptosis in vitro and antitumor effects in vivo. These results suggest that slightly pathogenic IAVs may prove to be effective for oncolytic virotherapy of PDA and provide grounds for further studies to develop specific and targeted viruses, with the aim of testing their efficacy in clinical contexts.

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Section: Discussionmentioning

confidence: 99%

Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

Kasloff

Pizzuto

Silic-Benussi

et al. 2014

J Virol

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“…Several studies demonstrated the type I interferon antagonist activity of NDV V protein with associated decrease in pathogenicity in recombinant viruses possessing attenuating mutations in the V protein or in viruses expressing lower V protein levels [37,38,44,46]. Recently, two studies demonstrated the role of the polymerase complex in viral pathogenesis, with L protein contributing to pathogenicity of the mesogenic Beaudette C strain, and NP, P, and L proteins contributing to pathogenicity of the velogenic Herts strain [42,43].…”

Section: Ndv Biology and Tropismmentioning

confidence: 99%

“…Further analysis of NDV infection in macrophages deleted for IRF-3 or IRF-7 revealed a significant increase in viral replication in IRF-3 KO macrophages, highlighting the important role of IRF-3 in initiating the innate anti-viral response to NDV [88]. Additional studies in a panel of tumor cell lines by Elankumaran et al demonstrated that most of the tested tumor cell lines in response to NDV infection failed to express IRF-7, while other cells were defective in induction of IFN-stimulated genes (ISG’s) such as RANTES, IP10, IRF-1, and ISG 6–16 (table 2) [46]. …”

Section: Mechanisms Of Ndv Specificity For Tumor Cells (Table 2)mentioning

confidence: 99%

Oncolytic Newcastle Disease Virus for Cancer Therapy: Old Challenges and New Directions

2012

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Summary Newcastle Disease Virus (NDV) is an avian paramyxovirus, which has been demonstrated to possess significant oncolytic activity against mammalian cancers. This review summarizes the research leading to the elucidation of the mechanisms of NDV-mediated oncolysis as well as the development of novel oncolytic agents through the use of genetic engineering. Clinical trials utilizing NDV strains and NDV-based autologous tumor cell vaccines will expand our knowledge of these novel anti-cancer strategies and will ultimately result in the successful use of the virus in the clinical setting.

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“…Despite agricultural concerns about NDV in poultry, the virus has been investigated as an oncolytic virus due to its inherent selective replication in tumor cells and associated cell death eliciting innate and adaptive antitumor immune responses (4). Prior to 2008, NDV had shown safety and some effectiveness in preclinical studies (5,6) and in human trials to treat a wide variety of tumor types (4,(7)(8)(9). The mechanism of NDV cancer cell selectivity is not entirely understood.…”

mentioning

confidence: 99%

Genetic Modification of Oncolytic Newcastle Disease Virus for Cancer Therapy

Cheng

Wang

et al. 2016

J Virol

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Clinical development of a mesogenic strain of Newcastle disease virus (NDV) as an oncolytic agent for cancer therapy has been hampered by its select agent status due to its pathogenicity in avian species. Using reverse genetics, we have generated a lead candidate oncolytic NDV based on the mesogenic NDV-73T strain that is no longer classified as a select agent for clinical development. This recombinant NDV has a modification at the fusion protein IMPORTANCEAvian paramyxovirus type 1, NDV, has been an attractive oncolytic agent for cancer virotherapy. However, this virus can cause epidemic disease in poultry, and concerns about the potential environmental and economic impact of an NDV outbreak have precluded its clinical development. Here we describe generation and characterization of a highly potent oncolytic NDV variant that is unlikely to cause Newcastle disease in its avian host, representing an essential step toward moving NDV forward as an oncolytic agent. Several attenuation mechanisms have been genetically engineered into the recombinant NDV that reduce chicken pathogenicity to a level that is acceptable worldwide without impacting viral production in cell culture. The selective tumor replication of this recombinant NDV, both in vitro and in vivo, along with efficient tumor cell killing makes it an attractive oncolytic virus candidate that may provide clinical benefit to patients.

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Type I Interferon-Sensitive Recombinant Newcastle Disease Virus for Oncolytic Virotherapy

Cited by 74 publications

References 44 publications

Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

Oncolytic Newcastle Disease Virus for Cancer Therapy: Old Challenges and New Directions

Genetic Modification of Oncolytic Newcastle Disease Virus for Cancer Therapy

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