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Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer
Abstract
Viruses have been engineered for cancer therapy in a variety of ways. Approaches include non-replicating gene therapy vectors, cancer vaccines and oncolytic viruses, but the clinical efficacy of these approaches has been limited by multiple factors. However, a new therapeutic class of oncolytic poxviruses has recently been developed that combines targeted and armed approaches for treating cancer. Initial preclinical and clinical results show that products from this therapeutic class can systemically target cancers in a highly selective and potent fashion using a multi-pronged mechanism of action.
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“Moreover, oncolytic viruses can be armed with vectors that encode for pro-inflammatory or anti-immunosuppressive transgenes, thereby in theory promoting both the immunogenicity of the tumour cells and intratumoral inflammation.128”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [128]
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“Vaccinia virus is highly immunogenic and has properties that make it an ideal oncolytic immunotherapy vector (7).”
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Liu, Y.-P., Wang, J., Avanzato, V. A., Bakkum-Gamez, J. N., Russell, S. J., Bell, J. C., & Peng, K.-W. (2014) · Gynecologic Oncology · doi:10.1016/j.ygyno.2014.01.009 · Cited by 18
“Interestingly, vaccine strains of VV have already been shown to inherently target cancer [33].”
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“First, OVV has a large viral genome that allows it to tolerate large foreign DNA fragments(10); second, the whole life cycle of OVV occurs in the cytoplasm of the host, thus preventing integration of the viral genome to the host genome(11); and third, viral thymidine kinase (TK)-deleted OVV shows attenuated replicatio…”
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“Myxoma virus (MV) is a rabbit-specific poxvirus pathogen that in the past few years has been intensely investigated as a potential oncolytic candidate [10-13].”
BackgroundTarget Therapy With Vaccinia Virus Harboring IL-24 For Human Breast Cancer
Deng, L., Fan, J. K., Ding, Y., Yang, X., Huang, B., & Hu, Z. (2019) · Journal of Cancer · doi:10.7150/jca.37590 · Cited by 18
“Oncolytic vaccinia virus represents a potential strategy for cancer therapy due to its appealing features such as extensive safety as a live vaccine and efficient delivery to metastatic tumors [2-4].”
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“CRAd, also called oncolytic adenovirus, is currently being developed as an attractive antitumor therapeutic in solid tumors including breast cancer [3–7].”
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“19 However, the fact that any infected cell would be destroyed as a result of viral replication meant that effective therapeutic transgenes would likely encode secreted proteins or peptides capable of producing a bystander killing effect.”
Self-citationStrategies for engineering oncolytic viruses to enhance cancer immunotherapy
Yin, Z. S., & Wang, Z. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1450203 · Cited by 17
“…to replicate independent of the host cell ’ s genome due to having its own RNA transcriptase and transcription factors within its viral core (Tolonen JX-594, Pexa-Vec (Kawai et al., 1988; Kirn and Thorne, 2009; Chan and McFadden, 2014; MacLeod et al., 2015; Jayawardena et al., 2020) et al., 2001).”
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“78 In pancreatic cancer, vaccinia has been genetically modified to increase the tumor cytotoxicity against pancreatic cancer.”
Trindade, G. D. S., Emerson, G. L., Sammons, S. R., Frace, M. A., Batra, D. G., Mota, B. E. F., Abrahão, J. S., de Assis, F. L., Olsen-Rasmussen, M. A., Goldsmith, C. S., et al. (2016) · Viruses · doi:10.3390/v8120328 · Cited by 17
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“cytotoxins, cytokines, prodrug converting enzymes and reporter genes that improved the overall performance of these viruses [1,2].”
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“…a conditionally replicating adenovirus (CRAd), also called oncolytic adenovirus, which exert intrinsic antitumor activity through selective replication in lysis cancer cells, causing the spread of progeny viruses in neighboring cancer cells, and eventually lysing the infected cancer cells (16-19).”
Current Strategies to Enhance Anti-Tumour Immunity
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“For JX-594 a mutation in the TK gene makes the virus cancer cell selective and human GM-CSF has been added to increase immunogenicity [83,84].”
BackgroundRojas, J. J., Hoecke, L. V., Conesa, M., Bueno-Merino, C., del Canizo, A., Riederer, S., Barcia, M., Brosinski, K., Lehmann, M. H., Volz, A., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.05.014 · Cited by 14
Functional insights into pathogen biology from 3D electron microscopy
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“Currently, vaccinia virus is used as a vaccine vector to target different diseases and in oncolytic therapies (Jacobs et al. 2009; Kirn and Thorne 2009; Thorne 2011; Walsh and Dolin 2011; Volz and Sutter 2013) and also as a probe to investigate cellular processes such as actin polymerisation or…”
BackgroundDeletion of immunomodulatory genes as a novel approach to oncolytic vaccinia virus development
Ho, T., Mealiea, D., Okamoto, L., Stojdl, D. F., & McCart, J. A. (2021) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2021.05.007 · Cited by 14
“It is well-established that OVs have multiple mechanisms of action against cancer including direct oncolysis, disruption of vasculature, and induction of anti-cancer immunity.(45) Immunohistochemistry results show that DK1L VV treatment increased T cell infiltration compared to mock-treatment even though neutrophil an…”
ResultOncolytic vaccinia virus: a silver bullet?
Lusky, M., Erbs, P., Foloppe, J., & Acres, R. B. (2010) · Expert Review of Vaccines · doi:10.1586/erv.10.137 · Cited by 14
Oncolytic Vaccinia Virus Therapy of Salivary Gland Carcinoma
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Gene therapy and nasopharyngeal carcinoma
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“However, to reach its target the vector would have to overcome clearance of circulating virus by complement and reticulo-endothelial cell-based mechanisms, which leads to phagocytosis of viral particles by macrophages or Kupffer cells (29) .”
BackgroundRecombinant Oncolytic Vaccinia Viruses Expressing Human β-Defensin 2 Enhance Anti-tumor Immunity
Sun, T., Luo, Y., Wang, M., Xie, T., & Yan, H. (2019) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2019.03.010 · Cited by 14
“It was also shown here that recombinant VVs with the deletion of the TK gene were preferentially toxic to tumor cell lines and were safe in normal cell lines (Figure 2A), because only cancer cells contain high concentrations of functional nucleotides that enable VVs to replicate after the deletion of viral thymidine k…”
ResultSturm, J. B., Heß, M., Weibel, S., Chen, N. G., Yu, Y., Zhang, Q., Donat, U., Reiß, C., Gambaryan, S. P., Krohne, G., et al. (2012) · Journal of Translational Medicine · doi:10.1186/1479-5876-10-9 · Cited by 14
“Among the currently investigated cancer therapies, the use of oncolytic vaccinia virus strains appear to be one of the most promising against a wide range of solid tumors [33].”
BackgroundAdvances in the use of nanoparticles for specific cell-target delivery of anti-cancer agents
Diaz-Ruano, A. B., Gomez-Jimenez, E., Llamas-Jimenez, G., Ramírez‐Muñoz, A., Espejo-Hijano, P., Rubio‐Navarro, A., & Picon‐Ruiz, M. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.123604 · Cited by 13
The Role of GM-CSF in Enhancing Immunotherapy of Cancer
Thorne, S. H. (2013) · Immunotherapy · doi:10.2217/imt.13.65 · Cited by 13
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Oncolytic gene therapy for canine cancers: teaching old dog viruses new tricks
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“Discussion Replication-competent VACVs are useful for the development of oncolytic viral therapies and elicit superior immune responses when used as vaccine and immunotherapeutic vectors (4, 26).”
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Capacity of wild-type and chemokine-armed parvovirus H-1PV for inhibiting neo-angiogenesis
Lavie, M., Struyf, S., Stroh-Dege, A., Rommelaere, J., Damme, J. V., & Dinsart, C. (2013) · Virology · doi:10.1016/j.virol.2013.09.019 · Cited by 13
“Recent reports show that oncolytic virus treatment results in tumor blood vessel coagulation and vasculature disruption (Breitbach et al., 2011, 2013) and may decrease the incidence of therapeutic resistance (Kirn and Thorne, 2009).”
BackgroundAdvances in cell-based delivery of oncolytic viruses as therapy for lung cancer
Nia, G. E., Nikpayam, E., Farrokhi, M., Bolhassani, A., & Meuwissen, R. L. J. (2024) · Molecular Therapy Oncology · doi:10.1016/j.omton.2024.200788 · Cited by 13
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“Pexa-Vec (JX-594, pexastimogene devacirepvec) is aWyeth strain oncolytic vaccinia virus engineered with viral thymidine kinase gene disruption and human granulocyte-macrophage colony-stimulating factor (hGM-CSF) transgene expression to favor replication selectivity for tumor cells and promote immune-activation.(6,7,15…”
BackgroundMethodGiving Oncolytic Vaccinia Virus More BiTE
Albelda, S. Μ., & Thorne, S. H. (2014) · Molecular Therapy · doi:10.1038/mt.2013.271 · Cited by 13
Self-citationThe impact of hypoxia on oncolytic virotherapy
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Vincent, D. I. W., Kramberger, P., Hudej, R., Štrancar, A., Wang, Y., Zhou, Y., & Velayudhan, A. (2017) · Journal of Chromatography A · doi:10.1016/j.chroma.2017.09.003 · Cited by 12
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Oncolytic Virotherapy in Solid Tumors: A Current Review
Chen, C., Cillis, J., Deshpande, S., Park, A. K., Valencia, H., Kim, S. I., Lu, J., Vashi, Y., Yang, A., Zhang, Z., et al. (2025) · BioDrugs · doi:10.1007/s40259-025-00743-z · Cited by 13
“Importantly, vaccinia can infect a wide range of cells due to the relatively forgiving cell entry process of endocytosis via cell membranes [72, 73].”
Oncolytic virotherapies for pediatric tumors
Gross, E. G., Hamo, M. A., Estévez-Ordoñez, D., Laskay, N. M. B., Atchley, T. J., Johnston, J. M., & Markert, J. M. (2023) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2023.2245326 · Cited by 11
“…modifications: (1) a deleted thymidine kinase gene for cancer-selective viral replication, (2) insertion of granulocyte macrophage colony-stimulating factor (GM-CSF) for immune stimulation, and (3) insertion of a β-galactosidase transgene to monitor the extent of viral replication [18,90,91].”
Lu, Y., Zhao, Y., Gao, C., Suresh, S., Men, J., Sawyers, A., & Smith, G. L. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.113788 · Cited by 11
“8,9 VACV encodes many proteins that block the innate immune response to infection, and these function at multiple levels.”
Design and Engineering of Deimmunized Vaccinia Viral Vectors
Song, K., & Viskovska, M. (2020) · Biomedicines · doi:10.3390/biomedicines8110491 · Cited by 11
“Strains highly specific to the tumor cells have been reported [27,28].”
BackgroundMa, J., Jin, C., Čančer, M., Wang, H., Ramachandran, M., & Yu, D. (2021) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2021.04.016 · Cited by 11
“VV was used as a vaccine against Variola, the causing virus of smallpox, and then developed also as a cancer vaccine or OV.6,7 It is an enveloped DNA virus, replicates in the cytoplasm.”
MethodNi, J., Hualin, F., Xu, X. M., Liu, T., Ye, T., Chen, K., & Li, G. (2021) · Marine Drugs · doi:10.3390/md19100532 · Cited by 11
Brun, J., Mahoney, D. J., Bœuf, F. L., Lefebvre, C. A., Sanaei, C. A., Falls, T. J., McCart, J. A., & Stojdl, D. F. (2012) · International Journal of Cancer · doi:10.1002/ijc.27695 · Cited by 11
“Finally, several of the Vaccinia virus variants used in this study were ‘armed’ with the cytokine GM-CSF, which has been shown to stimulate antitumor immunity.(21) Thus, immune awakening to tumor-associated antigens, released upon Vaccinia virus-mediated tumor cell lysis, may also have contributed to tumor resolution…”
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“VACV has been shown to act at three distinct levels [1].”
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Zhang, Y., Shi, X., Shen, Y., Dong, X., He, R., Chen, G., Zhang, Y., Tan, H., & Zhang, K. (2024) · MedComm · doi:10.1002/mco2.755 · Cited by 10
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Current strategies of virotherapy in clinical trials for cancer treatment
Lin, W., Zhao, Y., & Zhong, L. (2021) · Journal of Medical Virology · doi:10.1002/jmv.26947 · Cited by 10
Oncolytic Virotherapy and Immunogenic Cell Death: Mechanisms, Platforms, and Clinical Translation
Inoue, H. (2026) · Viruses · doi:10.3390/v18040461 · Cited by 10
Riederer, S., Fux, R., Lehmann, M. H., Volz, A., Sutter, G., & Rojas, J. J. (2021) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2021.06.001 · Cited by 9
“Among the various candidate viruses, vaccinia virus (VACV), the prototype human live virus vaccine used to eradicate smallpox,(13) displays several advantages as an oncolytic vector, including a fast and lytic replication cycle, an excellent human safety record, and high capacity for harboring transgenes.(14) Importan…”
BackgroundCytokines for the treatment of gastrointestinal cancers: clinical experience and new perspectives
Hernández-Alcoceba, R., Sangro, B., Berraondo, P., González‐Aseguinolaza, G., & Prìeto, J. (2013) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2013.793307 · Cited by 9
Virotherapy, gene transfer and immunostimulatory monoclonal antibodies
Quetglas, J. I., John, L. B., Kershaw, M. H., Álvarez‐Vallina, L., Melero, I., Darcy, P. K., & Smerdou, C. (2012) · OncoImmunology · doi:10.4161/onci.21679 · Cited by 9
“Vv is highly immunogenic and efficient at spreading through the blood to distal lesions upon the activation of signaling pathways such as that transduced by the epidermal growth factor receptor (EGFR)-RAS axis.(6,7) It is thought that the antitumor effects mediated by Vv are based on three different mechanisms of acti…”
BackgroundInfluentialNichols, A. C., Yoo, J. J., Um, S. H., Mundi, N., Palma, D. A., Fung, K., MacNeil, S. D., Koropatnick, J. D., Mymryk, J. S., & Barrett, J. W. (2013) · Intervirology · doi:10.1159/000353854 · Cited by 9
A non-replicating oncolytic vector as a novel therapeutic tool against cancer
Kaneda, Y. (2010) · BMB Reports · doi:10.5483/bmbrep.2010.43.12.773 · Cited by 9
Governa, V., Brittoli, A., Mele, V., Pinamonti, M., Terracciano, L., Muenst, S. E., Iezzi, G., Spagnoli, G. C., Zajac, P., & Trella, E. (2019) · OncoImmunology · doi:10.1080/2162402x.2019.1568162 · Cited by 9
“reagents upon systemic or intratumoral administration.(19) An oncolytic rVV expressing CD40L was recently shown to inhibit the growth of CD40+ human tumor cell xenografts in immunedeficient animals.”
BackgroundBéguin, J., Nourtier, V., Gantzer, M., Cochin, S., Foloppe, J., Balloul, J., Laloy, E., Tierny, D., Klonjkowski, B., Quéméneur, É., et al. (2020) · BMC Veterinary Research · doi:10.1186/s12917-020-02524-y · Cited by 9
In Vivo Oncolytic Virotherapy in Murine Models of Hepatocellular Carcinoma: A Systematic Review
Ailia, M. J., & Yoo, S. Y. (2022) · Vaccines · doi:10.3390/vaccines10091541 · Cited by 9
“VV has multiple anti-tumor mechanisms, including direct oncolysis, suppression of the immune response induced by tumors, and anti-angiogenesis [36,37].”
BackgroundEmerging gene-directed anti-tumor strategies against human hepatoblastoma
内山, 政., 奥村, 聰., 河上, 由., & 中川, 太. (2009) · Expert Opinion on Biological Therapy · doi:10.1517/14712590903136696 · Cited by 9
“(2009) 9(9) 1159 with a longstanding excellent safety record, and exhibit a potent natural oncolytic activity [59,60].”
BackgroundTreating Hepatobiliary Cancer: The Immunologic Approach
Duffy, A. G., & Greten, T. F. (2017) · Digestive Diseases · doi:10.1159/000456593 · Cited by 9
Oncolytic Virotherapy for Malignant Tumor: Current Clinical Status
Zhang, Y., & Liu, Z. (2019) · Current Pharmaceutical Design · doi:10.2174/1381612825666191104090544 · Cited by 9
The role of dendritic cells in neuroblastoma: Implications for immunotherapy
Zafari, R., Razi, S., & Rezaei, N. (2022) · Immunobiology · doi:10.1016/j.imbio.2022.152293 · Cited by 8
Autio, K., Knuuttila, A., Kipar, A., Ahonen, M., Parviainen, S., Diaconu, I., Kanerva, A., Hakonen, T., Vähä-Koskela, M. J. V., & Hemminki, A. (2014) · Veterinary and Comparative Oncology · doi:10.1111/vco.12119 · Cited by 8
Oncolytic virus as a cancer stem cell killer: progress and challenges.
Ding, J. (2014) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2306-9759.2014.12.02 · Cited by 8
“Such viruses fall into three broad categories: (I) wild-type viruses that do not typically infect human cells but are cytotoxic to human cancer cells; (II) attenuated viruses, either by mutations or serial passage, specifically targeting cancer cells; (III) larger viruses that can be armed to express transgenes (16,56…”
BackgroundWang, M., Luo, Y., Sun, T., Mao, C., Jiang, Y., Yu, X., Li, Z., Xie, T., Wu, F., Yan, H., et al. (2020) · OncoTargets and Therapy · doi:10.2147/ott.s230902 · Cited by 8
“whichhavehigher levels of nucleotides compared to the healthy, less replicative cells.(26,27) For its tumor cell selectivity and lower”
BackgroundFeng, Z., Xu, F., Liu, Y., Xu, H., Wu, F., Chen, X., & Xia, H. (2021) · Hepatoma Research · doi:10.20517/2394-5079.2020.107 · Cited by 8
Oncolytic Virotherapy of Cancer
Chen, N. G., & Szalay, A. A. (2010) · Springer eBooks · doi:10.1007/978-90-481-9704-0_16 · Cited by 8
“These oncolytic viruses include adenovirus [235], HSV [236], VACV [237], NDV [67], reovirus [60], measles virus [72], and coxsackievirus [185].”
BackgroundNot gene therapy, but genetic surgery—the right strategy to attack cancer
Sverdlov, E. D. (2009) · Molecular Genetics Microbiology and Virology · doi:10.3103/s089141680903001x · Cited by 9
Advances of oncolytic vaccinia viruses armed with interleukin in tumor therapy
Zha, M., Huang, F., Li, S., Wang, Q., & Tang, Y. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1594621 · Cited by 9
Thomas, R. J., Bartee, M. Y., Valenzuela-Cardenas, M., & Bartee, E. (2023) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2023.08.014 · Cited by 7
Mediation of antitumor activity by AZD4820 oncolytic vaccinia virus encoding IL-12
Kurokawa, C., Agrawal, S., Mitra, A., Galvani, E., Burke, S., Varshine, A., Rothstein, R. P., Schifferli, K. P., Monks, N. R., Foloppe, J., et al. (2024) · Molecular Therapy Oncology · doi:10.1016/j.omton.2023.200758 · Cited by 7
Immunotherapy of Hepatocellular Carcinoma
Sangro, B., Palmer, D. H., & Melero, I. (2014) · Hepatic Oncology · doi:10.2217/hep.14.16 · Cited by 7
Gene Therapy for Melanoma: Progress and Perspectives
Bryan, E., & Costanzi-Strauss, E. (2013) · InTech eBooks · doi:10.5772/54936 · Cited by 7
“The oncolytic poxvirus can also be armed, such as with the GM-CSF gene and with the bacterial β-galacto‐ sidase (LacZ) gene, serving as a marker for transduction as well as an antigen against which antibodies can be generated and measured [71].”
BackgroundAntiglioma Oncolytic Virotherapy: Unattainable Goal or a Success Story in the Making?
Dey, M., Auffinger, B., Lesniak, M. S., & Ahmed, A. U. (2013) · Future Virology · doi:10.2217/fvl.13.47 · Cited by 7
Advances in Therapeutic Approaches Using RNA Interference as a Gene Silencing Tool
Kaymaz, B. T., & Kosov, B. (2013) · Advanced Techniques in Biology & Medicine · doi:10.4172/2379-1764.1000108 · Cited by 7
Li, G., Mei, S., Cheng, J., Wu, T., & Luo, J. (2018) · Marine Drugs · doi:10.3390/md16050141 · Cited by 7
“Deletion of viral genes that are necessary for replication in nor al cells greatly enhanc s cancer cell-specific replication of oncolytic viruses [35].”
BackgroundInfluentialPeng, J., Wang, S., Fan, W., Li, S., Wu, Y., Mou, X., Wang, J., & Tong, X. (2018) · OncoTargets and Therapy · doi:10.2147/ott.s172037 · Cited by 7
“In addition, recent preclinical and clinical results have confirmed the potential of recombinant “armed” oVV in patients with end-stage cancers.(9,11,17) Inhibitor of growth family, member 4 (ING4) is a tumor suppressor which regulates the cell cycle, chromatin modification, cell proliferation, angiogenesis, and cell…”
BackgroundRetractedViral gene therapy for head and neck cancer
Hughes, J., Alusi, G., & Wang, Y. (2015) · The Journal of Laryngology & Otology · doi:10.1017/s0022215114003247 · Cited by 7
Development of bacterial nitroreductase enzymes for noninvasive imaging in cancer gene therapy
Williams, E. M. (2013) · Open Access Victoria University of Wellington | Te Herenga Waka (Figshare) · doi:10.26686/wgtn.17014019 · Cited by 7
Metadata
- Authors
- Kirn, D. H., & Thorne, S. H.
- ORCID
- Kirn, David H.
- Venue
- Nature Reviews Cancer
- Published
- 2009-01
- Volume
- 9
- Issue
- 1
- Pages
- 64-71
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- OpenAlex
- W2079647238
- Cited by
- 402
- References
- 134
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 19 · 2023: 14 · 2022: 16 · 2021: 16 · 2020: 20 · 2019: 14 · 2018: 16 · 2017: 24 · 2016: 25 · 2015: 29 · 2014: 29 · 2013: 49 · 2012: 36
- FWCI
- 2.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Immunology and Microbiology › Virology › Poxvirus research and outbreaks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Bacterial Cancer Therapy
- Keywords
- vaccinia virus, cancer gene therapy, cancer vaccines, viral vectors
- MeSH terms
- Animals, Forecasting, Humans, Immunity, Cellular, Inflammation, Neoplasm Metastasis, Neoplasms, Poxviridae, Vaccinia virus, Virus Replication, Gene Expression Regulation, Viral, Cancer Vaccines, Oncolytic Virotherapy, Oncolytic Viruses, Mice, Host-Pathogen Interactions
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