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Molecular Therapy Oncolytics

Marta Guerra-Rebollo, Carolina Nogueira de Moraes, Cristina Alcoholado, Carolina Soler-Botija, Lourdes Sanchez-Cid, Olaia F Vila, Oscar Meca-Cortés, Sara Ramos-Romero, Nuria Rubio, José Becerra, Jeronimo Blanco, Cristina Garrido
A preclinical model of glioblastoma (GB) bystander cell therapy using human adipose mesenchymal stromal cells (hAMSCs) is used to address the issues of cell availability, quality, and feasibility of tumor cure. We show that a fast proliferating variety of hAMSCs expressing thymidine kinase (TK) has therapeutic capacity equivalent to that of TK-expressing hAMSCs and can be used in a multiple-inoculation procedure to reduce GB tumors to a chronically inhibited state. We also show that up to 25% of unmodified hAMSCs can be tolerated in the therapeutic procedure without reducing efficacy...
December 21, 2018: Molecular Therapy Oncolytics
Michael P Phelps, Heechang Yang, Shivani Patel, Masmudur M Rahman, Grant McFadden, Eleanor Chen
Aberrant activation of the receptor tyrosine kinase-mediated RAS signaling cascade is the primary driver of embryonal rhabdomyosarcoma (ERMS), a pediatric cancer characterized by a block in myogenic differentiation. To investigate the cellular function of activated RAS signaling in regulating the growth and differentiation of ERMS cells, we genetically ablated activated RAS oncogenes with high-efficiency genome-editing technology. Knockout of NRAS in CRISPR-inducible ERMS xenograft models resulted in near-complete tumor regression through a combination of cell death and myogenic differentiation...
December 21, 2018: Molecular Therapy Oncolytics
Yibo Yin, Alina C Boesteanu, Zev A Binder, Chong Xu, Reiss A Reid, Jesse L Rodriguez, Danielle R Cook, Radhika Thokala, Kristin Blouch, Bevin McGettigan-Croce, Logan Zhang, Christoph Konradt, Alexandria P Cogdill, M Kazim Panjwani, Shuguang Jiang, Denis Migliorini, Nadia Dahmane, Avery D Posey, Carl H June, Nicola J Mason, Zhiguo Lin, Donald M O'Rourke, Laura A Johnson
We generated two humanized interleukin-13 receptor α2 (IL-13Rα2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13Rα2, but not IL-13Rα1. Hu08BBz also recognized canine IL-13Rα2. Both of these CAR T cell constructs demonstrated superior tumor inhibitory effects in a subcutaneous xenograft model of human glioma compared with a humanized EGFRvIII CAR T construct used in a recent phase 1 clinical trial ( NCT02209376). The Hu08BBz demonstrated a 75% reduction in orthotopic tumor growth using low-dose CAR T cell infusion...
December 21, 2018: Molecular Therapy Oncolytics
Jia-Ji Liu, Xuan Zhang, Xiao-Hou Wu
This study aimed to evaluate the effects of miR-93 on the growth and invasiveness of prostate cancer (PC) cells (PCCs). Real-time PCR was carried out to detect the expression of miR-93 in the PC tissues and cell lines. The adjacent normal tissues served as controls. For in vitro experiments, methyl thiazolyl tetrazolium, clone formation, tumor cell invasion assays, and western blot analysis (WBA) were performed to confirm the variations in the proliferation and invasiveness of PCCs, prior and subsequent to transfection with an miR-93 antisense oligonucleotide (ASO), which blocks miR-93 binding to its target...
December 21, 2018: Molecular Therapy Oncolytics
Amanda L Huff, Phonphimon Wongthida, Timothy Kottke, Jill M Thompson, Christopher B Driscoll, Matthew Schuelke, Kevin G Shim, Reuben S Harris, Amy Molan, Jose S Pulido, Peter J Selby, Kevin J Harrington, Alan Melcher, Laura Evgin, Richard G Vile
Tumor cells frequently evade applied therapies through the accumulation of genomic mutations and rapid evolution. In the case of oncolytic virotherapy, understanding the mechanisms by which cancer cells develop resistance to infection and lysis is critical to the development of more effective viral-based platforms. Here, we identify APOBEC3 as an important factor that restricts the potency of oncolytic vesicular stomatitis virus (VSV). We show that VSV infection of B16 murine melanoma cells upregulated APOBEC3 in an IFN-β-dependent manner, which was responsible for the evolution of virus-resistant cell populations and suggested that APOBEC3 expression promoted the acquisition of a virus-resistant phenotype...
December 21, 2018: Molecular Therapy Oncolytics
Zijiang Yang, Ting Zhang, Qiping Wang, Heng Gao
Pituitary adenomas constitute one of the most common intracranial tumors and are typically benign. However, the role of the tumor suppressor microRNA-34a (miR-34a), which is implicated in other cancers, in pituitary adenoma pathogenesis remains largely unknown. miR-34a expression was compared between GH4C1 cancer cells and normal cells derived from the pituitary gland of Rattus norvegicus , and the effects of miR-34a on GH4C1 cell proliferation and apoptosis were examined. miR-34a target genes were identified and analyzed computationally...
September 28, 2018: Molecular Therapy Oncolytics
Shawn T Beug, Stephanie J Pichette, Martine St-Jean, Janelle Holbrook, Danielle E Walker, Eric C LaCasse, Robert G Korneluk
Smac mimetic compounds (SMCs) are anti-cancer drugs that antagonize Inhibitor of Apoptosis proteins, which consequently sensitize cancer cells to death in the presence of proinflammatory ligands such as tumor necrosis factor alpha (TNF-α). SMCs synergize with the attenuated oncolytic vesicular stomatitis virus (VSVΔ51) by eliciting an innate immune response, which is dependent on the endogenous production of TNF-α and type I interferon. To improve on this SMC-mediated synergistic response, we generated TNF-α-armed VSVΔ51 to produce elevated levels of this death ligand...
September 28, 2018: Molecular Therapy Oncolytics
Victor Naumenko, Shinia Van, Himika Dastidar, Dae-Sun Kim, Seok-Joo Kim, Zhutian Zeng, Justin Deniset, Arthur Lau, Chunfen Zhang, Nicolas Macia, Belinda Heyne, Craig N Jenne, Douglas J Mahoney
Oncolytic virus (OV) therapy is an emerging cancer treatment that uses replicating viruses to infect and kill tumor cells and incite anticancer immunity. While the approach shows promise, it currently fails most patients, indicating strategies to improve OV activity are needed. Developing these will require greater understanding of OV biology, particularly in the context of OV delivery and clearance, the infection process within a complex tumor microenvironment, and the modulation of anticancer immunity. To help achieve this, we have established a technique for high-resolution 4D imaging of OV-host interactions within intact tissues of live mice using intravital microscopy (IVM)...
September 28, 2018: Molecular Therapy Oncolytics
Lukkana Suksanpaisan, Rong Xu, Mulu Z Tesfay, Carolyn Bomidi, Stefan Hamm, Rianna Vandergaast, Nathan Jenks, Michael B Steele, Ayuko Ota-Setlik, Hinna Akhtar, Amara Luckay, Rebecca Nowak, Kah Whye Peng, John H Eldridge, David K Clarke, Stephen J Russell, Rosa Maria Diaz
Immunotherapy for HPVPOS malignancies is attractive because well-defined, viral, non-self tumor antigens exist as targets. Several approaches to vaccinate therapeutically against HPV E6 and E7 antigens have been adopted, including viral platforms such as VSV. A major advantage of VSV expressing these antigens is that VSV also acts as an oncolytic virus, leading to direct tumor cell killing and induction of effective anti-E6 and anti-E7 T cell responses. We have also shown that addition of immune adjuvant genes, such as IFNβ, further enhances safety and/or efficacy of VSV-based oncolytic immunovirotherapies...
September 28, 2018: Molecular Therapy Oncolytics
Otto Hemminki, Minna Oksanen, Kristian Taipale, Ilkka Liikanen, Anniina Koski, Timo Joensuu, Anna Kanerva, Akseli Hemminki
The first US Food and Drug Administration (FDA)- and EMA-approved oncolytic virus has been available since 2015. However, there are no markers available that would predict benefit for the individual patient. During 2007-2012, we treated 290 patients with advanced chemotherapy-refractory cancers, using 10 different oncolytic adenoviruses. Treatments were given in a Finnish Medicines Agency (FIMEA)-regulated individualized patient treatment program (the Advanced Therapy Access Program [ATAP]), which required long-term follow-up of patients, which is presented here...
June 29, 2018: Molecular Therapy Oncolytics
Nicola E Annels, Mehreen Arif, Guy R Simpson, Mick Denyer, Carla Moller-Levet, David Mansfield, Rachel Butler, Darren Shafren, Gough Au, Margaret Knowles, Kevin Harrington, Richard Vile, Alan Melcher, Hardev Pandha
As a clinical setting in which local live biological therapy is already well established, non-muscle invasive bladder cancer (NMIBC) presents intriguing opportunities for oncolytic virotherapy. Coxsackievirus A21 (CVA21) is a novel intercellular adhesion molecule-1 (ICAM-1)-targeted immunotherapeutic virus. This study investigated CVA21-induced cytotoxicity in a panel of human bladder cancer cell lines, revealing a range of sensitivities largely correlating with expression of the viral receptor ICAM-1. CVA21 in combination with low doses of mitomycin-C enhanced CVA21 viral replication and oncolysis by increasing surface expression levels of ICAM-1...
June 29, 2018: Molecular Therapy Oncolytics
Iris Scherwitzl, Alicia Hurtado, Carolyn M Pierce, Sandra Vogt, Christine Pampeno, Daniel Meruelo
Oncolytic viruses represent a promising form of cancer immunotherapy. We investigated the potential of Sindbis virus (SV) for the treatment of solid tumors expressing the human cancer testis antigen NYESO-1. NYESO-1 is an immunogenic antigen frequently expressed in numerous cancers, such as ovarian cancer. We show that SV expressing the tumor-associated antigen NYESO-1 (SV-NYESO1) acts as an immunostimulatory agent, inducing systemic and rapid lymphocyte activation, leading to a pro-inflammatory environment...
June 29, 2018: Molecular Therapy Oncolytics
Mathias Felix Leber, Marc-Andrea Baertsch, Sophie Caroline Anker, Luisa Henkel, Hans Martin Singh, Sascha Bossow, Christine E Engeland, Russell Barkley, Birgit Hoyler, Jessica Albert, Christoph Springfeld, Dirk Jäger, Christof von Kalle, Guy Ungerechts
Measles viruses derived from the live-attenuated Edmonton-B vaccine lineage are currently investigated as novel anti-cancer therapeutics. In this context, tumor specificity and oncolytic potency are key determinants of the therapeutic index. Here, we describe a systematic and comprehensive analysis of a recently developed post-entry targeting strategy based on the incorporation of microRNA target sites (miRTS) into the measles virus genome. We have established viruses with target sites for different microRNA species in the 3' untranslated regions of either the N , F , H , or L genes and generated viruses harboring microRNA target sites in multiple genes...
June 29, 2018: Molecular Therapy Oncolytics
Michael P O'Leary, Susanne G Warner, Sang-In Kim, Shyambabu Chaurasiya, Jianming Lu, Audrey H Choi, Anthony K Park, Yanghee Woo, Yuman Fong, Nanhai G Chen
This study hypothesizes that a novel oncolytic chimeric orthopoxvirus CF33-Fluc is imageable and targets colorectal cancer cells (CRCs). A novel chimeric orthopoxvirus (CF33) was constructed. The thymidine kinase locus was replaced with firefly luciferase (Fluc) to yield a recombinant virus-CF33-Fluc. In vitro cytotoxicity and viral replication assays were performed. In vivo CRC flank xenografts received single doses of intratumoral or intravenous CF33-Fluc. Viral biodistribution was analyzed via luciferase imaging and organ titers...
June 29, 2018: Molecular Therapy Oncolytics
Audrey H Choi, Michael P O'Leary, Jianming Lu, Sang-In Kim, Yuman Fong, Nanhai G Chen
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high recurrence rate and poor prognosis. Here, we describe a novel, chimeric orthopoxvirus (CF33) that efficiently kills TNBC. Cytotoxicity was assayed in vitro in four TNBC cell lines. Viral replication was examined through standard plaque assay. Two orthotopic TNBC xenograft models were generated in athymic nude mice and were injected with CF33 intratumorally. CF33 was effective in vitro with potent cytotoxicity and efficient intracellular replication observed in TNBC lines with phosphatidylinositol 3-kinase (PI3K)/Akt pathway mutations that resulted in endogenous phospho-Akt (p-Akt) activity (BT549, Hs578T, and MDA-MB-468)...
June 29, 2018: Molecular Therapy Oncolytics
Hannah M Burgess, Aldo Pourchet, Cristina H Hajdu, Luis Chiriboga, Alan B Frey, Ian Mohr
Through the action of two virus-encoded decapping enzymes (D9 and D10) that remove protective caps from mRNA 5'-termini, Vaccinia virus (VACV) accelerates mRNA decay and limits activation of host defenses. D9- or D10-deficient VACV are markedly attenuated in mice and fail to counter cellular double-stranded RNA-responsive innate immune effectors, including PKR. Here, we capitalize upon this phenotype and demonstrate that VACV deficient in either decapping enzyme are effective oncolytic viruses. Significantly, D9- or D10-deficient VACV displayed anti-tumor activity against syngeneic mouse tumors of different genetic backgrounds and human hepatocellular carcinoma xenografts...
March 30, 2018: Molecular Therapy Oncolytics
Ahmed Abdullah Al-Zaher, Rafael Moreno, Carlos Alberto Fajardo, Marcel Arias-Badia, Martí Farrera, Jana de Sostoa, Luis Alfonso Rojas, Ramon Alemany
To enhance adenovirus-mediated oncolysis, different approaches that tackle the selectivity, tumor penetration, and spreading potential of oncolytic adenoviruses have been reported. We have previously demonstrated that insertion of the internalizing Arginine-Glycine-Aspartic (iRGD) tumor-penetrating peptide at the C terminus of the fiber or transgenic expression of a secreted hyaluronidase can improve virus tumor targeting and spreading. Here we report a new oncolytic adenovirus ICOVIR17K-iRGD in which both modifications have been incorporated...
March 30, 2018: Molecular Therapy Oncolytics
Faizule Hassan, Shuisong Ni, Tyler C Arnett, Melanie C McKell, Michael A Kennedy
High mobility group AT-hook 1 (HMGA1) protein is an oncogenic architectural transcription factor that plays an essential role in early development, but it is also implicated in many human cancers. Elevated levels of HMGA1 in cancer cells cause misregulation of gene expression and are associated with increased cancer cell proliferation and increased chemotherapy resistance. We have devised a strategy of using engineered viruses to deliver decoy hyper binding sites for HMGA1 to the nucleus of cancer cells with the goal of sequestering excess HMGA1 at the decoy hyper binding sites due to binding competition...
March 30, 2018: Molecular Therapy Oncolytics
Gray Kueberuwa, Milena Kalaitsidou, Eleanor Cheadle, Robert Edward Hawkins, David Edward Gilham
Chimeric antigen receptor (CAR) T cell therapy represents a significant advancement in cancer therapy. Larger studies have shown ∼90% complete remission rates against chemoresistant and/or refractory CD19+ leukemia or lymphoma. Effective CAR T cell therapy is highly dependent on lymphodepleting preconditioning, which is achieved through chemotherapy or radiotherapy that carries with it significant toxicities. These can exclude patients of low performance status. In order to overcome the need for preconditioning, we constructed fully mouse first and second generation anti-murine CD19 CARs with or without interleukin-12 (IL-12) secretion...
March 30, 2018: Molecular Therapy Oncolytics
Ernesto Mejías-Pérez, Liliana Carreño-Fuentes, Mariano Esteban
Despite the effectiveness of classic treatments and available diagnostic tools, cancer continues to be a leading world health problem, with devastating cancer-related death rates. Advances in oncolytic virotherapy have shown promise as potentially effective treatment options in the fight against cancer. The poxviruses have many features that make them an attractive platform for the development of oncolytic vectors, with some candidates currently in clinical trials. Here, we report the design and generation of a new oncolytic vector based on the vaccinia virus Western Reserve (WR) strain...
March 30, 2018: Molecular Therapy Oncolytics
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