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Molecular Therapy Oncolytics

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https://www.readbyqxmd.com/read/28875159/myxoma-virus-optimizes-cisplatin-for-the-treatment-of-ovarian-cancer-in%C3%A2-vitro-and-in-a-syngeneic-murine-dissemination-model
#1
Bernice Nounamo, Jason Liem, Martin Cannon, Jia Liu
A therapeutic approach to improve treatment outcome of ovarian cancer (OC) in patients is urgently needed. Myxoma virus (MYXV) is a candidate oncolytic virus that infects to eliminate OC cells. We found that in vitro MYXV treatment enhances cisplatin or gemcitabine treatment by allowing lower doses than the corresponding IC50 calculated for primary OC cells. MYXV also affected OC patient ascites-associated CD14(+) myeloid cells, one of the most abundant immunological components of the OC tumor environment; without causing cell death, MYXV infection reduces the ability of these cells to secrete cytokines such as IL-10 that are signatures of the immunosuppressive tumor environment...
September 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28856238/reovirus-fast-protein-enhances-vesicular-stomatitis-virus-oncolytic-virotherapy-in-primary-and-metastatic-tumor-models
#2
Fabrice Le Boeuf, Simon Gebremeskel, Nichole McMullen, Han He, Anna L Greenshields, David W Hoskin, John C Bell, Brent Johnston, Chungen Pan, Roy Duncan
The reovirus fusion-associated small transmembrane (FAST) proteins are the smallest known viral fusogens (∼100-150 amino acids) and efficiently induce cell-cell fusion and syncytium formation in multiple cell types. Syncytium formation enhances cell-cell virus transmission and may also induce immunogenic cell death, a form of apoptosis that stimulates immune recognition of tumor cells. These properties suggest that FAST proteins might serve to enhance oncolytic virotherapy. The oncolytic activity of recombinant VSVΔM51 (an interferon-sensitive vesicular stomatitis virus [VSV] mutant) encoding the p14 FAST protein (VSV-p14) was compared with a similar construct encoding GFP (VSV-GFP) in cell culture and syngeneic BALB/c tumor models...
September 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28856237/t-cell-activating-mesenchymal-stem-cells-as-a-biotherapeutic-for-hcc
#3
Arpad Szoor, Abishek Vaidya, Mireya Paulina Velasquez, Zhuyong Mei, Daniel L Galvan, David Torres, Adrian Gee, Andras Heczey, Stephen Gottschalk
The outcome for advanced stage hepatocellular carcinoma (HCC) remains poor, highlighting the need for novel therapies. Genetically modified mesenchymal stem cells (MSCs) are actively being explored as cancer therapeutics due to their inherent ability to migrate to tumor sites. We reasoned that MSCs can be genetically modified to redirect T cells to Glypican-3 (GPC3)(+) HCC, and genetically modified these with viral vectors encoding a GPC3/CD3 bispecific T cell engager (GPC3-ENG), a bispecifc T cell engager specific for an irrelevant antigen (EGFRvIII), and/or costimulatory molecules (CD80 and 41BBL)...
September 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28808676/efficacy-and-safety-of-doubly-regulated-vaccinia-virus-in-a-mouse-xenograft-model-of-multiple-myeloma
#4
Muneyoshi Futami, Kota Sato, Kanji Miyazaki, Kenshi Suzuki, Takafumi Nakamura, Arinobu Tojo
Multiple myeloma is a malignancy of plasma cells of the bone marrow. Although the prognosis is variable, no curative therapy has been defined. Vaccinia virus infects cancer cells and kills such cells in a variety of ways. These include direct infection, triggering of immunomediated cell death, and vascular collapse. The potential of the vaccinia virus as an anti-tumor therapy has attracted the attention of oncologists. Interestingly, our preliminary experiments revealed that myeloma cells were particularly susceptible to vaccinia virus...
September 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28748212/genetically-engineered-multilineage-differentiating-stress-enduring-cells-as-cellular-vehicles-against-malignant-gliomas
#5
Tomohiro Yamasaki, Shohei Wakao, Hiroshi Kawaji, Shinichiro Koizumi, Tetsuro Sameshima, Mari Dezawa, Hiroki Namba
Malignant glioma, the most common malignant brain tumor in adults, is difficult to treat due to its aggressive invasive nature. Enzyme/prodrug suicide gene therapy based on the herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) system is an efficient strategy for treating malignant gliomas. In the present study, we evaluated treatment with multilineage-differentiating stress-enduring (Muse) cells, which are endogenous non-tumorigenic pluripotent-like stem cells that are easily collectable from the bone marrow as SSEA-3(+) cells, as carriers of the HSVtk gene...
September 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28736743/oncolytic-adenovirus-loaded-menstrual-blood-stem-cells-overcome-the-blockade-of-viral-activity-exerted-by-ovarian-cancer-ascites
#6
Ana Laura Alfano, Alejandro Nicola Candia, Nicasio Cuneo, Leandro N Guttlein, Alejandro Soderini, Cecilia Rotondaro, Leonardo Sganga, Osvaldo L Podhajcer, M Veronica Lopez
Patients with ovarian cancer present peritoneal ascites at recurrence as a marker of disseminated disease and dismal prognosis. Oncolytic immunotherapy is an emerging approach for the treatment of disseminated cancer. In the present work, we constructed a novel oncolytic adenovirus, AR2011, to target malignant ovarian tumors. AR2011 exhibited a clear lytic effect in vitro in human ovarian cancer cell lines and malignant cells obtained from ascitic fluids (AFs) of patients with ovarian cancer. AR2011 activity was neutralized by antibodies present in 31 samples of patient-derived AFs...
September 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28649600/oncolytic-herpes-virus-rrp450-shows-efficacy-in-orthotopic-xenograft-group-3-4-medulloblastomas-and-atypical-teratoid-rhabdoid-tumors
#7
Adam W Studebaker, Brian J Hutzen, Christopher R Pierson, Kellie B Haworth, Timothy P Cripe, Eric M Jackson, Jeffrey R Leonard
Pediatric brain tumors including medulloblastoma and atypical teratoid/rhabdoid tumor are associated with significant mortality and treatment-associated morbidity. While medulloblastoma tumors within molecular subgroups 3 and 4 have a propensity to metastasize, atypical teratoid/rhabdoid tumors frequently afflict a very young patient population. Adjuvant treatment options for children suffering with these tumors are not only sub-optimal but also associated with many neurocognitive obstacles. A potentially novel treatment approach is oncolytic virotherapy, a developing therapeutic platform currently in early-phase clinical trials for pediatric brain tumors and recently US Food and Drug Administration (FDA)-approved to treat melanoma in adults...
September 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28607950/chemovirotherapy-of-pancreatic-adenocarcinoma-by-combining-oncolytic-vaccinia-virus-glv-1h68-with-nab-paclitaxel-plus-gemcitabine
#8
Eike Binz, Susanne Berchtold, Julia Beil, Martina Schell, Christine Geisler, Irina Smirnow, Ulrich M Lauer
Oncolytic viruses have proven their therapeutic potential against a variety of different tumor entities both in vitro and in vivo. Their ability to selectively infect and lyse tumor cells, while sparing healthy tissues, makes them favorable agents for tumor-specific treatment approaches. Particularly, the addition of virotherapeutics to already established chemotherapy protocols (so-called chemovirotherapy) is of major interest. Here we investigated the in vitro cytotoxic effect of the oncolytic vaccinia virus GLV-1h68 combined with dual chemotherapy with nab-paclitaxel plus gemcitabine in four human pancreatic adenocarcinoma cell lines (AsPc-1, BxPc-3, MIA-PaCa-2, and Panc-1)...
September 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28607949/non-glycanated-decorin-is-a-drug-target-on-human-adipose-stromal-cells
#9
Alexes C Daquinag, Ali Dadbin, Brad Snyder, Xiaoping Wang, Aysegul A Sahin, Naoto T Ueno, Mikhail G Kolonin
Adipose stromal cells (ASCs) have been identified as a mesenchymal cell population recruited from white adipose tissue (WAT) by tumors and supporting cancer progression. We have previously reported the existence of a non-glycanated decorin isoform (ngDCN) marking mouse ASCs. We identified a peptide CSWKYWFGEC that binds to ngDCN and hence can serve as a vehicle for ASC-directed therapy delivery. We used hunter-killer peptides composed of CSWKYWFGEC and a pro-apoptotic moiety to deplete ASCs and suppress growth of mouse tumors...
September 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28812060/reolysin-and-histone-deacetylase-inhibition-in-the-treatment-of-head-and-neck-squamous-cell-carcinoma
#10
Alena C Jaime-Ramirez, Jun-Ge Yu, Enrico Caserta, Ji Young Yoo, Jianying Zhang, Tae Jin Lee, Craig Hofmeister, John H Lee, Bhavna Kumar, Quintin Pan, Pawan Kumar, Robert Baiocchi, Theodoros Teknos, Flavia Pichiorri, Balveen Kaur, Matthew Old
Oncolytic viruses (OVs) are emerging as powerful anti-cancer agents and are currently being tested for their safety and efficacy in patients. Reovirus (Reolysin), a naturally occurring non-pathogenic, double-stranded RNA virus, has natural oncolytic activity and is being tested in phase I-III clinical trials in a variety of tumor types. With its recent US Food and Drug Administration (FDA) orphan drug designation for several tumor types, Reolysin is a potential therapeutic agent for various cancers, including head and neck squamous cell carcinomas (HNSCCs), which have a 5-year survival of ∼55%...
June 16, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28573185/hcv-t-cell-receptor-chain-modifications-to-enhance-expression-pairing-and-antigen-recognition-in-t-cells-for-adoptive-transfer
#11
Kendra C Foley, Timothy T Spear, David C Murray, Kaoru Nagato, Elizabeth Garrett-Mayer, Michael I Nishimura
T cell receptor (TCR)-gene-modified T cells for adoptive cell transfer can mediate objective clinical responses in melanoma and other malignancies. When introducing a second TCR, mispairing between the endogenous and introduced α and β TCR chains limits expression of the introduced TCR, which can result in impaired efficacy or off-target reactivity and autoimmunity. One approach to promote proper TCR chain pairing involves modifications of the introduced TCR genes: introducing a disulfide bridge, substituting murine for human constant regions, codon optimization, TCR chain leucine zipper fusions, and a single-chain TCR...
June 16, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28573184/a-comparative-study-of-replication-incompetent-and-competent-adenoviral-therapy-mediated-immune-response-in-a-murine-glioma-model
#12
Julius W Kim, Jason Miska, Jacob S Young, Aida Rashidi, J Robert Kane, Wojciech K Panek, Deepak Kanojia, Yu Han, Irina V Balyasnikova, Maciej S Lesniak
Oncolytic virotherapy is a treatment approach with increasing clinical relevance, as indicated by the marked survival benefit seen in animal models and its current exploration in human patients with cancer. The use of an adenovirus vector for this therapeutic modality is common, has significant clinical benefit in animals, and its efficacy has recently been linked to an anti-tumor immune response that occurs following tumor antigen presentation. Here, we analyzed the adaptive immune system's response following viral infection by comparing replication-incompetent and replication-competent adenoviral vectors...
June 16, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28547002/oncolytic-herpes-simplex-virus-inhibits-pediatric-brain-tumor-migration-and-invasion
#13
Julia V Cockle, Anke Brüning-Richardson, Karen J Scott, Jill Thompson, Timothy Kottke, Ewan Morrison, Azam Ismail, Angel M Carcaboso, Ailsa Rose, Peter Selby, Joe Conner, Susan Picton, Susan Short, Richard Vile, Alan Melcher, Elizabeth Ilett
Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are invasive tumors with poor survival. Oncolytic virotherapy, initially devised as a direct cytotoxic treatment, is now also known to act via immune-mediated mechanisms. Here we investigate a previously unreported mechanism of action: the inhibition of migration and invasion in pediatric brain tumors. We evaluated the effect of oncolytic herpes simplex virus 1716 (HSV1716) on the migration and invasion of pHGG and DIPG both in vitro using 2D (scratch assay, live cell imaging) and 3D (spheroid invasion in collagen) assays and in vivo using an orthotopic xenograft model of DIPG invasion...
June 16, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28480328/preclinical-safety-studies-of-enadenotucirev-a-chimeric-group-b-human-specific-oncolytic-adenovirus
#14
Sam Illingworth, Ying Di, Maxine Bauzon, Janet Lei, Margaret R Duffy, Simon Alvis, Brian Champion, André Lieber, Terry Hermiston, Len W Seymour, John Beadle, Kerry Fisher
Enadenotucirev is an oncolytic group B adenovirus identified by a process of bio-selection for the ability to selectively propagate in and rapidly kill carcinoma cells. It is resistant to inactivation by human blood components, potentially enabling intravenous dosing in patients with metastatic cancer. However, there are no known permissive animal models described for group B adenoviruses that could facilitate a conventional approach to preclinical safety studies. In this manuscript, we describe our tailored preclinical strategy designed to evaluate the key biological properties of enadenotucirev...
June 16, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28480327/humanized-mice-with-subcutaneous-human-solid-tumors-for-immune-response-analysis-of-vaccinia-virus-mediated-oncolysis
#15
Desislava Tsoneva, Boris Minev, Alexa Frentzen, Qian Zhang, Anja K Wege, Aladar A Szalay
Oncolytic vaccinia virus (VACV) therapy is an alternative cancer treatment modality that mediates targeted tumor destruction through a tumor-selective replication and an induction of anti-tumor immunity. We developed a humanized tumor mouse model with subcutaneous human tumors to analyze the interactions of VACV with the developing tumors and human immune system. A successful systemic reconstitution with human immune cells including functional T cells as well as development of tumors infiltrated with human T and natural killer (NK) cells was observed...
June 16, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28480326/combining-oncolytic-virotherapy-with-p53-tumor-suppressor-gene-therapy
#16
REVIEW
Christian Bressy, Eric Hastie, Valery Z Grdzelishvili
Oncolytic virus (OV) therapy utilizes replication-competent viruses to kill cancer cells, leaving non-malignant cells unharmed. With the first U.S. Food and Drug Administration-approved OV, dozens of clinical trials ongoing, and an abundance of translational research in the field, OV therapy is poised to be one of the leading treatments for cancer. A number of recombinant OVs expressing a transgene for p53 (TP53) or another p53 family member (TP63 or TP73) were engineered with the goal of generating more potent OVs that function synergistically with host immunity and/or other therapies to reduce or eliminate tumor burden...
June 16, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28480325/the-sequence-of-delta24-rgd-and-tmz-administration-in-malignant-glioma-affects-the-role-of-cd8-t-cell-anti-tumor-activity
#17
Anne Kleijn, Wouter van den Bossche, Erik S Haefner, Zineb Belcaid, Chantal Burghoorn-Maas, Jenneke J Kloezeman, Suzan D Pas, Sieger Leenstra, Reno Debets, Jeroen de Vrij, Clemens M F Dirven, Martine L M Lamfers
The conditionally replicating oncolytic adenovirus Delta24-RGD (Ad) is currently under investigation in clinical trials for glioblastoma, including in combination with temozolomide (TMZ), the standard chemotherapy for this tumor. Previously, we showed that the efficacy of Delta24-RGD in a murine model is primarily dependent on the virus-induced anti-tumor immune response. As observed with most chemotherapies, TMZ has pronounced immune-modulating effects. Here, we studied the combined effects of these treatments in a murine glioma model...
June 16, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28345027/pre-clinical-assessment-of-c134-a-chimeric-oncolytic-herpes-simplex-virus-in-mice-and-non-human-primates
#18
Kevin A Cassady, David F Bauer, Justin Roth, Melissa R Chambers, Trent Shoeb, Jennifer Coleman, Mark Prichard, G Yancey Gillespie, James M Markert
Oncolytic herpes simplex virus (oHSV) type I constructs are investigational anti-neoplastic agents for a variety of malignancies, including malignant glioma. Clinical trials to date have supported the safety of these agents even when directly administered in the CNS. Traditional pre-clinical US Food and Drug Administration (FDA) toxicity studies for these agents have included the use of two species, generally including murine and primate studies. Recently, the FDA has decreased its requirement of non-human primates as an animal model for ethical reasons, especially for established viral systems where there are good alternative model systems...
June 16, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28345026/oncolytic-adenoviruses-armed-with-tumor-necrosis-factor-alpha-and-interleukin-2-enable-successful-adoptive-cell-therapy
#19
Riikka Havunen, Mikko Siurala, Suvi Sorsa, Susanna Grönberg-Vähä-Koskela, Michael Behr, Siri Tähtinen, João Manuel Santos, Pauliina Karell, Juuso Rusanen, Dirk M Nettelbeck, Anja Ehrhardt, Anna Kanerva, Akseli Hemminki
Adoptive cell therapy holds much promise in the treatment of cancer but results in solid tumors have been modest. The notable exception is tumor-infiltrating lymphocyte (TIL) therapy of melanoma, but this approach only works with high-dose preconditioning chemotherapy and systemic interleukin (IL)-2 postconditioning, both of which are associated with toxicities. To improve and broaden the applicability of adoptive cell transfer, we constructed oncolytic adenoviruses coding for human IL-2 (hIL2), tumor necrosis factor alpha (TNF-α), or both...
March 17, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28345025/optimization-of-a-neural-stem-cell-mediated-carboxylesterase-irinotecan-gene-therapy-for-metastatic-neuroblastoma
#20
Margarita Gutova, Leanne Goldstein, Marianne Metz, Anahit Hovsepyan, Lyudmila G Tsurkan, Revathiswari Tirughana, Lusine Tsaturyan, Alexander J Annala, Timothy W Synold, Zesheng Wan, Robert Seeger, Clarke Anderson, Rex A Moats, Philip M Potter, Karen S Aboody
Despite improved survival for children with newly diagnosed neuroblastoma (NB), recurrent disease is a significant problem, with treatment options limited by anti-tumor efficacy, patient drug tolerance, and cumulative toxicity. We previously demonstrated that neural stem cells (NSCs) expressing a modified rabbit carboxylesterase (rCE) can distribute to metastatic NB tumor foci in multiple organs in mice and convert the prodrug irinotecan (CPT-11) to the 1,000-fold more toxic topoisomerase-1 inhibitor SN-38, resulting in significant therapeutic efficacy...
March 17, 2017: Molecular Therapy Oncolytics
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