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Molecular Therapy Oncolytics

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https://www.readbyqxmd.com/read/29511732/adenovirus-mediated-delivery-of-decoy-hyper-binding-sites-targeting-oncogenic-hmga1-reduces-pancreatic-and-liver-cancer-cell-viability
#1
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
https://www.readbyqxmd.com/read/29367945/cd19-car-t-cells-expressing-il-12-eradicate-lymphoma-in-fully-lymphoreplete-mice-through-induction-of-host-immunity
#2
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
https://www.readbyqxmd.com/read/29367944/development-of-a-safe-and-effective-vaccinia-virus-oncolytic-vector-wr-%C3%AE-4-with-a-set-of-gene-deletions-on-several-viral-pathways
#3
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
https://www.readbyqxmd.com/read/29322091/a-retroviral-replicating-vector-encoding-cytosine-deaminase-and-5-fc-induces-immune-memory-in-metastatic-colorectal-cancer-models
#4
Kader Yagiz, Maria E Rodriguez-Aguirre, Fernando Lopez Espinoza, Tiffany T Montellano, Daniel Mendoza, Leah A Mitchell, Carlos E Ibanez, Noriyuki Kasahara, Harry E Gruber, Douglas J Jolly, Joan M Robbins
Treatment of tumors with Toca 511, a gamma retroviral replicating vector encoding cytosine deaminase, followed by 5-fluorocytosine (5-FC) kills tumors by local production of 5-fluorouracil (5-FU). In brain tumor models, this treatment induces systemic anti-tumor immune responses and long-term immune-mediated survival. Phase 1 Toca 511 and Toca FC (extended-release 5-FC) clinical trials in patients with recurrent high-grade glioma show durable complete responses and promising survival data compared to historic controls...
March 30, 2018: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/29234727/the-dual-role-of-bone-morphogenetic-proteins-in-cancer
#5
REVIEW
Duc-Hiep Bach, Hyen Joo Park, Sang Kook Lee
Bone morphogenetic proteins (BMPs) are a diverse class of molecules with over 20 growth factor proteins that belong to the transforming growth factor-β (TGF-β) family and are highly associated with bone formation and disease development. Aberrant expression of various BMPs has been reported in several cancer tissues. Biological function studies have elicited the dual role of BMPs in both cancer development and suppression. Furthermore, a variety of BMP antagonists, ligands, and receptors have been shown to reduce or enhance tumorigenesis and metastasis...
March 30, 2018: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/29367943/using-cystine-knot-proteins-as-a-novel-approach-to-retarget-oncolytic-measles-virus
#6
Sangeet Lal, Corey Raffel
Modified measles virus (MV) has effective oncolytic activity preclinically and is currently being investigated in clinical trials for various types of cancer. We investigated the use of cystine knot proteins (CKPs) to direct MV activity. CKPs are short polypeptides that bind their targets with high affinity. We used a CKP that binds αvβ3, αvβ5, and α5β1 integrins with single-digit nanomolar affinity to retarget MV to the integrins (MV-CKPint). MV-CKPint infected, replicated in, and killed human glioblastoma, medulloblastoma, diffuse intrinsic pontine glioma (DIPG), and melanoma cancer cells in vitro, all of which express the target integrins...
December 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/29202008/suppression-of-oncolytic-adenovirus-mediated-hepatotoxicity-by-liver-specific-inhibition-of-nf-%C3%AE%C2%BAb
#7
Mitsuhiro Machitani, Fuminori Sakurai, Keisaku Wakabayashi, Kosuke Nakatani, Masashi Tachibana, Nobuyuki Kato, Toshiyoshi Fujiwara, Hiroyuki Mizuguchi
Telomerase-specific replication-competent adenoviruses (Ads), i.e., TRADs, which possess an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, are promising agents for cancer treatment. However, even though oncolytic Ads, including TRAD, are intratumorally administered, they are disseminated from the tumor to systemic circulation, causing concern about oncolytic Ad-mediated hepatotoxicity (due mainly to leaky expression of Ad genes in liver). We reported that inhibition of nuclear factor-κB (NF-κB) leads to the suppression of replication-incompetent Ad vector-mediated hepatotoxicity via reduction of the leaky expression of Ad genes in liver...
December 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/29159280/insertion-of-the-type-i-ifn-decoy-receptor-b18r-in-a-mirna-tagged-semliki-forest-virus-improves-oncolytic-capacity-but-results-in-neurotoxicity
#8
Tina Sarén, Mohanraj Ramachandran, Miika Martikainen, Di Yu
Oncolytic Semliki Forest virus (SFV) has been suggested as a potential candidate for the treatment of glioblastoma and neuroblastoma. However, the oncolytic capacity of SFV is restricted by the anti-viral type-I interferon (IFN) response. The aim of this study was to increase the oncolytic capacity of a microRNA target tagged SFV against glioblastoma by arming it with the Vaccinia-virus-encoded type-I IFN decoy receptor B18R (SFV4B18RmiRT) to neutralize type-I IFN response. Expression of B18R by SFV4B18RmiRT aided neutralization of IFN-β, which was shown by reduced STAT-1 phosphorylation and improved virus spread in plaque assays...
December 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/29062886/activating-peripheral-innate-immunity-enables-safe-and-effective-oncolytic-virotherapy-in-the-brain
#9
Lukxmi Balathasan, Vera A Tang, Beta Yadollahi, Jan Brun, Melanie Labelle, Charles Lefebvre, Stephanie L Swift, David F Stojdl
The oncolytic mutant vesicular stomatitis virus VSVΔ51 achieves robust efficacy in multiple extracranial tumor models. Yet for malignancies of the brain, direct intratumoral infusion of VSVΔ51 causes lethal virus-induced neuropathology. Here, we have developed a novel therapeutic regime that uses peripheral immunization with a single sub-lethal dose of VSVΔ51 to establish an acute anti-viral state that enables the safe intracranial (IC) infusion of an otherwise lethal dose of VSVΔ51 within just 6 hr. Although type I interferons alone appeared insufficient to explain this protective phenotype, serum isolated at early time points from primed animals conferred protection against an IC dose of virus...
December 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/29034314/targeting-an-oncolytic-influenza-a-virus-to-tumor-tissue-by-elastase
#10
Irina Kuznetsova, Tobias Arnold, Thomas Aschacher, Cornelia Schwager, Balazs Hegedus, Tamas Garay, Marina Stukova, Maria Pisareva, Stephan Pleschka, Michael Bergmann, Andrej Egorov
Oncolytic viruses are currently established as a novel type of immunotherapy. The challenge is to safely target oncolytic viruses to tumors. Previously, we have generated influenza A viruses (IAVs) containing deletions in the viral interferon antagonist. Those deletions have attenuated the virus in normal tissue but allowed replication in tumor cells. IAV entry is mediated by hemagglutinin (HA), which needs to be activated by a serine protease, for example, through trypsin. To further target the IAV to tumors, we have changed the trypsin cleavage site to an elastase cleavage site...
December 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/29034313/newly-characterized-murine-undifferentiated-sarcoma-models-sensitive-to-virotherapy-with-oncolytic-hsv-1-m002
#11
Eric K Ring, Rong Li, Blake P Moore, Li Nan, Virginia M Kelly, Xiaosi Han, Elizabeth A Beierle, James M Markert, Jianmei W Leavenworth, G Yancey Gillespie, Gregory K Friedman
Despite advances in conventional chemotherapy, surgical techniques, and radiation, outcomes for patients with relapsed, refractory, or metastatic soft tissue sarcomas are dismal. Survivors often suffer from lasting morbidity from current treatments. New targeted therapies with less toxicity, such as those that harness the immune system, and immunocompetent murine sarcoma models to test these therapies are greatly needed. We characterized two new serendipitous murine models of undifferentiated sarcoma (SARC-28 and SARC-45) and tested their sensitivity to virotherapy with oncolytic herpes simplex virus 1 (HSV-1)...
December 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/29034312/tgf-%C3%AE-inhibition-improves-oncolytic-herpes-viroimmunotherapy-in-murine-models-of-rhabdomyosarcoma
#12
Brian Hutzen, Chun-Yu Chen, Pin-Yi Wang, Les Sprague, Hayley M Swain, Julia Love, Joe Conner, Louis Boon, Timothy P Cripe
Oncolytic viruses are an emerging class of cancer therapeutics that couple cytotoxicity with the induction of an anti-tumor immune response. Host-virus interactions are complex and modulated by a tumor microenvironment whose immunosuppressive activities can limit the effectiveness of cancer immunotherapies. In an effort to improve this aspect of oncolytic virotherapy, we combined the oncolytic herpes virus HSV1716 with the transforming growth factor beta receptor 1 (TGF-βR1) inhibitor A8301 to treat syngeneic models of murine rhabdomyosarcoma...
December 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28951885/cowpox-virus-a-new-and-armed-oncolytic-poxvirus
#13
Marine Ricordel, Johann Foloppe, Christelle Pichon, Nathalie Sfrontato, Delphine Antoine, Caroline Tosch, Sandrine Cochin, Pascale Cordier, Eric Quemeneur, Christelle Camus-Bouclainville, Stéphane Bertagnoli, Philippe Erbs
Oncolytic virus therapy has recently been recognized as a promising new therapeutic approach for cancer treatment. In this study, we are proposing for the first time to evaluate the in vitro and in vivo oncolytic capacities of the Cowpox virus (CPXV). To improve the tumor selectivity and oncolytic activity, we developed a thymidine kinase (TK)-deleted CPXV expressing the suicide gene FCU1, which converts the non-toxic prodrug 5-fluorocytosine (5-FC) into cytotoxic 5-fluorouracil (5-FU) and 5-fluorouridine-5'-monophosphate (5-FUMP)...
December 15, 2017: Molecular Therapy Oncolytics
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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