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Strategies and Challenges to Arming Oncolytic Viruses with Therapeutic Genes Terry W Hermiston and Irene Kuhn Berlex Biosciences, Richmond, California 94804-0099, USA

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Strategies and Challenges to Arming Oncolytic Viruses with Therapeutic Genes Terry W Hermiston and Irene Kuhn Berlex Biosciences, Richmond, California 94804-0099, USA Cancer Gene Therapy (2002) 9, 1022 – 1035 D 2002 Nature Publishing Group All rights reserved 0929-1903/02 $25.00 www.nature.com/cgt Review Armed therapeutic viruses: Strategies and challenges to arming oncolytic viruses with therapeutic genes Terry W Hermiston and Irene Kuhn Berlex Biosciences, Richmond, California 94804-0099, USA. Oncolytic viruses are attractive therapeutics for cancer because they selectively amplify, through replication and spread, the input dose of virus in the target tumor. To date, clinical trials have demonstrated marked safety but have not realized their theoretical efficacy potential. In this review, we consider the potential of armed therapeutic viruses, whose lytic potential is enhanced by genetically engineered therapeutic transgene expression from the virus, as potential vehicles to increase the potency of these agents. Several classes of therapeutic genes are outlined, and potential synergies and hurdles to their delivery from replicating viruses are discussed. Cancer Gene Therapy (2002) 9, 1022–1035 doi:10.1038/sj.cgt.7700542 Keywords: oncolytic virus; armed therapeutic virus; gene therapy; cancer umor-selective, replication-competent oncolytic vi- Three strategies are being pursued to overcome this weak- Truses offer several unique features as cancer therapeu- ness. One is to create less attenuated (more potent) viruses tics. First, the input dose is amplified in a tumor-dependent either through use of alternative viruses or by employing fashion. Consequently, even if only a small proportion of the alternative, less attenuating, mechanisms for restricting input dose infects some of the target tumor cells, this replication to tumor cells.1–3 The second is to employ infective dose should be capable of replicating in and additional cytotoxic mechanisms, beyond the direct lytic eliminating neoplastic cells, using successive waves of functions of the virus, by arming these viruses with replication and lysis until the tumor mass is completely therapeutic genes.4 Particularly attractive in this context are destroyed. Importantly, these tumor-selective replication those cytotoxic mechanisms with potent bystander effects competent viruses spare normal tissue. Because replication- capable of eliminating tumor cells that the virus cannot selective oncolytic viruses do not replicate efficiently in reach. And the third is to combine the oncolytic viral therapy normal cells, the associated toxicities should be low. This with the more traditional radiotherapy and/or chemotherapy, property will become critical for systemic viral delivery to with which virotherapies often synergize.5 treat metastatic disease. Low toxicity creates an opportunity This review will summarize current clinical results with for the investigator to increase the dose of the therapeutic replication-selective oncolytic viruses (Table 1). We will virus to overcome losses associated with nonspecific uptake examine gene therapy strategies using nonreplicating viral or neutralization due to specific (e.g., antibodies) and vectors, as these inform current strategies for improving nonspecific (e.g., albumin) factors. With their capacity to be oncolytic therapies. Particular focus will be given to carried passively throughout the body via the blood or lymph strategies for arming oncolytic viruses with therapeutic circulatory systems, these agents should be able to reach, genes capable of eliciting antitumor immune function, infect, and similarly eliminate all metastatic lesions. These inhibition of tumor neovascularization, or prodrug activa- replication-competent, tumor-specific oncolytic viruses tion. Through synergistic combination of several cytotoxic offer hope in the daunting field of cancer therapy. modalities (viral lysis, immune or antiangiogenic function, A number of replication-competent, tumor-selective surgery and/or chemo- and radiotherapy), therapies capable oncolytic viruses have entered the clinic. Clinical experi- of eradicating tumors may be generated. ences show that these agents are safe, but are not potent enough as monotherapies to effect complete tumor regres- sions or to generate sustained clinical responses. Insufficient Oncolytic viruses or inefficient infection of tumor cells is generally observed. Since the early 1900s, reports of tumor regression correlating with either viral vaccination or infection have peaked interest Received September 18, 2002. in the oncolytic potential of viruses. The first clinical trial of Address correspondence and reprint requests to: Dr Terry W Hermiston replicating viruses (using wild-type adenoviruses) was done 6 Berlex Biosciences, 2600 Hilltop Avenue, PO Box 4099, Richmond, CA in 1956. There are suggestions of efficacy in the results of 94804-0099, USA. E-mail: [email protected] that trial, but lack of understanding of both the disease and Table 1 Oncolytic viruses Viral agent Genetic alteration Target tissue or cell pathway Therapeutic gene Indication Stage of clinical development Reference Adenoviruses ONYX-015 (dl1520) E1B–55 kDa deletion p53 – Head and neck Phase III [3,6,104–108] Ovarian cancer Phase I Colorectal cancer Phases I–II Pancreatic cancer Phase I Hepatocellular Phase I Carcinoma Phases I–II Ad5-CD/TKrep E1B–55 kDa deletion p53 CD/TK fusion Prostate cancer Phase I [30,109] rc Ad.TK (II) E1B–55 kDa deletion p53 TK Colon cancer – [110] TW Hermiston and IArmed Kuhn therapeutic viruses dl922–947 E1A mutation Rb pathway – Solid tumors – [111] Á24 E1A mutation Rb pathway – Solid tumors – [112,113] E1Adl01/07 E1A mutation Proliferating cells – Solid tumors – [114] KD1, KD3 E1A mutation Proliferating cells, – Solid tumors – [115] immunoprivileged state of tumor KD1-SPB E1A mutation/promoter Proliferating cells, – Lung cancer – [116] driving E4 immunoprivileged state of tumor CV706 PSA promoter-driven E1A Prostate – Prostate cancer Phases I–II [117,118] CV787 Probasin-driven Prostate – Prostate cancer Phases I–II [119] E1A and PSA-driven E1B vcF11 Tcf4-driven E1A and E4 Colon – Colon cancer – [120] ONYX-411 E2F-driven E1A and E4 Rb pathway – Solid tumors – [1] AvE1a04i a-Fetoprotein–driven E1A Liver – Hepatocellular – [121] carcinoma Cancer Gene Therapy ONYX-304 E3–gp19 kDa deletion Immunoprivileged state CD Solid tumors – [89] of tumor ONYX-323 E3-gp19 kDa deletion Immunoprivileged state TNF Solid tumors – [89] of tumor IG.Ad5E1( + ). E3TK E3-gp19 kDa deletion Immunoprivileged state TK Solid tumors – [96] of tumor AdTyrÁ24, Tyrosinase promoter-driven Melanoma – Melanoma – [122] AdTyrÁ2Á24 mutant E1A 1023 1024 Cancer Gene Therapy Ad.Flk-1, Ad.Flk-Endo Flk promoter-driven; Dividing endothelium – Solid tumors – [53] E1A±endogilin promoter-driven E1B 01/PEME p53-responsive p53 – Solid tumors – [123] promoter-driven E2F antagonist to control E1A and E2A expression AdE2F-1CRc E2F promoter-driven E1A Proliferating cells – Solid tumors – [124] AdAFPep/Rep AFP promoter-driving p53 – Hapatocellular – [125] E1A 13S, carcinoma E1B–55 kDa deleted Adl118 E1B deleted p53 – Breast cancer – [126] Ad.DF3-E1 DF3/MUC1 MUC1-positive TNF Breast cancer – [86] promoter-driven E1A human carcinomas TW Hermiston and I Kuhn Adp53rc ADP deletion Unclear p53 Solid tumors – [22] Armed therapeutic viruses HSVÀderived viruses G207 g34.5 and ICP6 deletion Proliferating cells, IFN – Malignant glioma Phases I–II [8,127] 1716 g34.5 deletion Proliferating cells, IFN – Malignant glioma Phase I [9,128] NV1020 (R7020) g34.5 deletion Proliferating cells, IFN – Solid tumors Phase I [129] 3616UB Uracil DNA glycosylase Proliferating cells, IFN – Solid tumors – [130] and g34.5 deletion M002 g34.5 deletion Proliferating cells, IFN IL-12 Solid tumors – [131] Fu-10 g34.5 and ICP6 deletion, Proliferating cells, IFN – Solid tumors – [132] selected for syncytial formation rRp450 ICP6 deleted Proliferating cells CYP2B1 Colon cancer – [133,134] hrR3 ICP6 deleted Proliferating cells – Solid tumors – [135,136] dvB7Ig/G207 g34.5 and ICP6 deletion Proliferating cells, IFN Soluble B7-1 Solid tumors – [137] G92A Albumin promoter-driven ICP4 Liver – Hepatocellular – [138] carcinoma G47Á g34.5, ICP6, and Proliferating cells, IFN, – Solid tumors – [137] ICP47 deleted immunoprivileged state of tumor dlsp+K TK deleted Proliferating cells – Solid tumors – [139] R8306 g34.5 deleted Proliferating cells, IFN IL-4 Solid tumors – [85] Myb34.5 ICP6 deleted, Proliferating cells, IFN – Solid tumors – [140] B-myb promoter driving g34.5 (continued on next page) Table 1 (continued ) Viral agent Genetic alteration Target tissue or cell pathway Therapeutic gene Indication Stage of clinical development Reference NV1034 g34.5 deleted Proliferating cells, IFN GM-CSF Solid tumors – [87] NV1042 g34.5 deleted Proliferating cells, IFN IL-12 Solid tumors – [87] HSV1yCD ICP6 deleted Proliferating cells CD Solid tumors – [141] g34.5 deleted Proliferating cells, IFN – Solid tumors – [142] Newcastle disease virus PV701 Passage attenuated IFN – Solid tumors Phases I–II [10] Vaccinia Various names TK deleted Proliferating cells – Solid tumors – [143–146] Vaccinia/GM-CSF RV TK deleted Proliferating cells GM-CSF Melanoma Phase I [147] VvEMAP TK deleted Proliferating cells EMAP-II Melanoma – [148] VV-IL-2 TK deleted Proliferating cells IL-2 Malignant Phase I [149] mesothelioma VMPPNP TK deleted Proliferating cells PNP Solid tumors – [144] VvCD TK deleted Proliferating cells CD Colon cancer – [148] Various names TK deleted Proliferating cells B7-1, ICAM-1, Solid tumors [150] and LFA-3 alone and references therein TW Hermiston and IArmed Kuhn therapeutic
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