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Oncolytic viral therapy

L A Rojas, R Moreno, H Calderón, R Alemany
There is great skepticism in the capability of adenovirus vectors and oncolytic adenoviruses to reach specific organs or tumors upon systemic administration. Besides antibodies, the presence of CAR (coxsackie and adenovirus receptor) in human erythrocytes has been postulated to sequester CAR-binding adenoviruses, commonly used in gene therapy and oncolytic applications. The use of non-CAR-binding fibers or serotypes has been postulated to solve this limitation. Given the lack of integrins in erythrocytes and therefore of internalization of the CAR-bound virus, we hypothesized that the interaction of adenovirus type 5 (Ad5) with CAR in human erythrocytes could be reversible...
October 21, 2016: Cancer Gene Therapy
Mitsuhiro Machitani, Fuminori Sakurai, Keisaku Wakabayashi, Masashi Tachibana, Toshiyoshi Fujiwara, Hiroyuki Mizuguchi
Oncolytic viruses have been receiving much attention as potential agents for cancer treatment. Among the various types of oncolytic viruses, the telomerase-specific replication-competent adenovirus (TRAD), which carries the tumor-specific promoter-driven E1 gene expression cassette, exhibits efficient antitumor effects. The development of a novel TRAD that shows higher replication efficiency and antitumor activity would be highly beneficial for safer and more efficient cancer therapy. We recently demonstrated that the endoribonuclease Dicer significantly inhibits the replication of wild-type adenovirus (Ad) via the processing of viral-associated (VA)-RNAs, which are Ad-encoded small noncoding RNAs, and that the knockdown of Dicer leads to enhanced VA-RNA expression and Ad replication after infection with wild-type Ad...
October 19, 2016: Molecular Cancer Therapeutics
Catherine Dold, Carles Rodriguez Urbiola, Guido Wollmann, Lisa Egerer, Alexander Muik, Lydia Bellmann, Heidelinde Fiegl, Christian Marth, Janine Kimpel, Dorothee von Laer
Previously, we described an oncolytic vesicular stomatitis virus variant pseudotyped with the nonneurotropic glycoprotein of the lymphocytic choriomeningitis virus, VSV-GP, which was highly effective in glioblastoma. Here, we tested its potency for the treatment of ovarian cancer, a leading cause of death from gynecological malignancies. Effective oncolytic activity of VSV-GP could be demonstrated in ovarian cancer cell lines and xenografts in mice; however, remission was temporary in most mice. Analysis of the innate immune response revealed that ovarian cancer cell lines were able to respond to and produce type I interferon, inducing an antiviral state upon virus infection...
2016: Molecular Therapy Oncolytics
Galina Kochneva, Galina Sivolobova, Anastasiya Tkacheva, Antonina Grazhdantseva, Olga Troitskaya, Anna Nushtaeva, Anastasiya Tkachenko, Elena Kuligina, Vladimir Richter, Olga Koval
Vaccinia virus (VACV) oncolytic therapy has been successful in a number of tumor models. In this study our goal was to generate a double recombinant vaccinia virus (VV-GMCSF-Lact) with enhanced antitumor activity that expresses exogenous proteins: the antitumor protein lactaptin and human granulocyte-macrophage colony-stimulating factor (GM-CSF). Lactaptin has previously been demonstrated to act as a tumor suppressor in mouse hepatoma as well as MDA-MB-231 human adenocarcinoma cells grafted into SCID mice. VV-GMCSF-Lact was engineered from Lister strain (L-IVP) vaccinia virus and has deletions of the viral thymidine kinase and vaccinia growth factor genes...
September 30, 2016: Oncotarget
Hasan Rehman, Ann W Silk, Michael P Kane, Howard L Kaufman
With the recent regulatory approval of Talimogene laherparepvec (T-VEC) for the treatment of advanced of melanoma in the United States, Europe and Australia, oncolytic virus immunotherapy has earned its place in the clinic. However, the adoption of T-VEC by the U.S. oncology community has been slow, and so far has been largely limited to specialized cancer centers. Limiting factors include the intratumoral route of administration, which is unfamiliar to medical oncologists, biosafety concerns related to the use of a live virus in the clinic, and the explosion of other therapeutic strategies now available for the treatment of advanced melanoma...
2016: Journal for Immunotherapy of Cancer
Alan E Bilsland, Pavlina Spiliopoulou, T R Jeffry Evans
For decades, effective cancer gene therapy has been a tantalising prospect; for a therapeutic modality potentially able to elicit highly effective and selective responses, definitive efficacy outcomes have often seemed out of reach. However, steady progress in vector development and accumulated experience from previous clinical studies has finally led the field to its first licensed therapy. Following a pivotal phase III trial, Imlygic (talimogene laherparepvec/T-Vec) received US approval as a treatment for cutaneous and subcutaneous melanoma in October 2015, followed several weeks later by its European authorisation...
2016: F1000Research
Jiahu Wang, Rozanne Arulanandam, Richard Wassenaar, Theresa Falls, Julia Petryk, Judith Paget, Kenneth Garson, Catia Cemeus, Barbara Vanderhyden, Glenn Wells, John Bell, Fabrice Le Boeuf
PURPOSE: Oncolytic virus (OV) therapy has emerged as a novel tool in our therapeutic arsenals for fighting cancer. As a live biological agent, oncolytic virus has the ability to target and selectively amplify at the tumor sites. We have reported that a vaccinia-based OV (Pexa-Vec) has shown good efficacy in pre-clinical models and in clinical trials. In order to give an additional tool to clinicians to allow both treatment of the tumor and improved visualization of tumor margins, we developed new viral based platforms with two specific gene reporters...
September 15, 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Jie Shi, Shengjun Fu, Li Wang, Yan Tao, Ronald Rodriguez, Zhiping Wang
Our previous work confirmed that the bladder cancer-specific oncolytic adenovirus Ad/PSCAE/UPII/E1A could selectively replicate in bladder cancer cells, thus causing specific tumor cell lysis. The replicative potential is a crucial factor in determining the therapeutic efficacy of oncolytic adenoviruses. However, viral replication is attenuated by the low-activity promoter that we used, thus compromising viral cytotoxicity. In this study, we investigated the effect of the cell cycle-dependent kinase inhibitor p21/Waf-1 on an adenovirus...
September 12, 2016: Anti-cancer Drugs
George E Naoum, Fady Tawadros, Ammad Ahmad Farooqi, Muhammad Zahid Qureshi, Sobia Tabassum, Donald J Buchsbaum, Waleed Arafat
Since its identification as a member of the tumour necrosis factor (TNF) family, TRAIL (TNF-related apoptosis-inducing ligand) has emerged as a new avenue in apoptosis-inducing cancer therapies. Its ability to circumvent the chemoresistance of conventional therapeutics and to interact with cancer stem cells (CSCs) self-renewal pathways, amplified its potential as a cancer apoptotic agent. Many recombinant preparations of this death ligand and monoclonal antibodies targeting its death receptors have been tested in monotherapy and combinational clinical trials...
2016: Ecancermedicalscience
Kei X Tan, Michael K Danquah, Amandeep Sidhu, Clarence M Ongkudon, Sie Yon Lau
Cancer is a leading cause of global mortality. Whilst anticancer awareness programs have increased significantly over the years, scientific research into the development of efficient and specific drugs to target cancerous cells for enhanced therapeutic effects has not received much clinical success. Chemotherapeutic agents are incapable of acting specifically on cancerous cells, thus causing low therapeutic effects accompanied by toxicity to surrounding normal tissues. The search for smart, highly specific and efficient cancer treatments and delivery systems continues to be a significant research endeavor...
September 1, 2016: European Journal of Pharmaceutical Sciences
Katrina Sweeney, Gunnel Halldén
Prostate cancer is a leading cause of cancer-related death and morbidity in men in the Western world. Tumor progression is dependent on functioning androgen receptor signaling, and initial administration of antiandrogens and hormone therapy (androgen-deprivation therapy) prevent growth and spread. Tumors frequently develop escape mechanisms to androgen-deprivation therapy and progress to castration-resistant late-stage metastatic disease that, in turn, inevitably leads to resistance to all current therapeutics, including chemotherapy...
2016: Oncolytic Virotherapy
A O Sosnovtceva, N F Grinenko, A V Lipatova, P M Chumakov, V P Chekhonin
Effective treatment of malignant brain tumors is still an open problem. Location of tumor in vital areas of the brain significantly limits capasities of surgical treatment. The presence of tumor stem cells resistant to radiation and anticancer drugs in brain tumor complicates use of chemoradiotherapy and causes a high rate of disease recurrence. A technological improvement in bioselection and production of recombinant resulted in creation of viruses with potent oncolytic properties against glial tumors. Recent studies, including clinical trials, showed, that majority of oncolytic viruses are safe...
May 2016: Biomedit︠s︡inskai︠a︡ Khimii︠a︡
Elena P Goncharova, Julia S Ruzhenkova, Ivan S Petrov, Sergey N Shchelkunov, Marina A Zenkova
BACKGROUND: Tumour resistance to a wide range of drugs (multiple drug resistant, MDR) acquired after intensive chemotherapy is considered to be the main obstacle of the curative treatment of cancer patients. Recent work has shown that oncolytic viruses demonstrated prominent potential for effective treatment of diverse cancers. Here, we evaluated whether genetically modified vaccinia virus (LIVP-GFP) may be effective in treatment of cancers displaying MDR phenotype. METHODS: LIVP-GFP replication, transgene expression and cytopathic effects were analysed in human cervical carcinomas KB-3-1 (MDR-), KB-8-5 (MDR+) and in murine melanoma B-16 (MDR-), murine lymphosarcomas RLS and RLS-40 (MDR+)...
2016: Journal of Translational Medicine
Lianwen Zhang, Michael B Steele, Nathan Jenks, Jacquelyn Grell, Lukkana Suksanpaisan, Shruthi Naik, Mark J Federspiel, Martha Q Lacy, Stephen J Russell, Kah-Whye Peng
Oncolytic VSV-IFNβ-NIS is selectively destructive to tumors. Here, we present the IND enabling preclinical rodent studies in support of clinical testing of vesicular stomatitis virus (VSV) as a systemic therapy. Efficacy studies showed dose-dependent tumor regression in C57BL/KaLwRij mice bearing syngeneic 5TGM1 plasmacytomas after systemic VSV administration. In contrast, the virus was effective at all doses tested against human KAS6/1 xenografts in SCID mice. Intravenous administration of VSV-mIFNβ-NIS is well tolerated in C57BL/6 mice up to 5 × 10(10) TCID50 (50% tissue culture infective dose)/kg with no neurovirulence, no cytokine storm, and no abnormalities in tissues...
September 2016: Human Gene Therapy. Clinical Development
Dipongkor Saha, Hiroaki Wakimoto, Samuel D Rabkin
Oncolytic viruses (OVs), like oncolytic herpes simplex virus (oHSV), are genetically engineered to selectively replicate in and kill cancer cells, while sparing normal cells. Initial OV infection, cell death, and subsequent OV propagation within the tumor microenvironment leads to a cascade of host responses (innate and adaptive), reflective of natural anti-viral immune responses. These host-virus interactions are critical to the balance between OV activities, anti-viral immune responses limiting OV, and induction of anti-tumor immunity...
August 3, 2016: Current Opinion in Virology
Brian A Keller, John C Bell
The oncolytic virus (OV) field has entered an exciting period in its evolution in which our basic understanding of viral biology and anti-cancer potential are being actively translated into viable therapeutic options for aggressive malignancies. OVs are naturally occurring or engineered viruses that are able to exploit cancer-specific changes in cellular signaling to specifically target cancers and their microenvironment. The direct cytolytic effect of OVs on cancer cells is known to release antigens, which can begin a cascade of events that results in the induction of anti-cancer adaptive immunity...
September 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Hiroshi Fukuhara, Yasushi Ino, Tomoki Todo
Oncolytic virus therapy is perhaps the next major breakthrough in cancer treatment following the success in immunotherapy using immune checkpoint inhibitors. Oncolytic viruses are defined as genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells without harming the normal tissues. T-Vec (talimogene laherparepvec), a second-generation oncolytic herpes simplex virus type 1 (HSV-1) armed with GM-CSF, was recently approved as the first oncolytic virus drug in the USA and Europe...
August 3, 2016: Cancer Science
Janaina Fernandes
The transforming properties of oncogenes are derived from gain-of-function mutations, shifting cell signaling from highly regulated homeostatic to an uncontrolled oncogenic state, with the contribution of the inactivating mutations in tumor suppressor genes P53 and RB, leading to tumor resistance to conventional and target-directed therapy. On the other hand, this scenario fulfills two requirements for oncolytic virus infection in tumor cells: inactivation of tumor suppressors and presence of oncoproteins, also the requirements to engage malignancy...
2016: Biomarkers in Cancer
Lorrie A Burnham, Dinesh Jaishankar, Jeffrey M Thompson, Kevin S Jones, Deepak Shukla, Vaibhav Tiwari
Cationic liposomes are widely used to facilitate introduction of genetic material into target cells during transfection. This study describes a non-receptor mediated herpes simplex virus type-1 (HSV-1) entry into the Chinese hamster ovary (CHO-K1) cells that naturally lack glycoprotein D (gD)-receptors using a commercially available cationic liposome: lipofectamine. Presence of cell surface heparan sulfate (HS) increased the levels of viral entry indicating a potential role of HS in this mode of entry. Loss of viral entry in the presence of actin de-polymerizing or lysosomotropic agents suggests that this mode of entry results in the endocytosis of the lipofectamine-virus mixture...
2016: Frontiers in Microbiology
Sean E Lawler, Maria-Carmela Speranza, Choi-Fong Cho, E Antonio Chiocca
Importance: Oncolytic viruses (OVs) are emerging as important agents in cancer treatment. Oncolytic viruses offer the attractive therapeutic combination of tumor-specific cell lysis together with immune stimulation, therefore acting as potential in situ tumor vaccines. Moreover, OVs can be engineered for optimization of tumor selectivity and enhanced immune stimulation and can be readily combined with other agents. The effectiveness of OVs has been demonstrated in many preclinical studies and recently in humans, with US Food and Drug Administration approval of the oncolytic herpesvirus talimogene laherparepvec in advanced melanoma, a major breakthrough for the field...
July 21, 2016: JAMA Oncology
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