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Molecular Therapy Oncolytics

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https://www.readbyqxmd.com/read/28480328/preclinical-safety-studies-of-enadenotucirev-a-chimeric-group-b-human-specific-oncolytic-adenovirus
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
https://www.readbyqxmd.com/read/28345024/ovad1-a-novel-potent-and-selective-chimeric-oncolytic-virus-developed-for-ovarian-cancer-by-3d-directed-evolution
#8
Irene Kuhn, Maxine Bauzon, Nicola Green, Len Seymour, Kerry Fisher, Terry Hermiston
Effective therapeutics for ovarian cancer continue to be urgently needed, particularly for chemotherapy-resistant cases. Here we present both a 3D-Matrigel culture-based expansion of our directed evolution method for generation of oncolytic virotherapies and two promising ovarian-cancer targeted oncolytic viruses, OvAd1 and OvAd2. OvAd1 was developed using Matrigel cell cultures, whereas OvAd2 was developed in parallel using traditional monolayer tissue culture methods. Both viruses are potent against a panel of platinum-resistant ovarian cancer cell lines and are attenuated on normal cells in vitro, resulting in therapeutic windows of ∼200-fold...
March 17, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28345023/enhancement-of-psma-directed-car-adoptive-immunotherapy-by-pd-1-pd-l1-blockade
#9
Inna Serganova, Ekaterina Moroz, Ivan Cohen, Maxim Moroz, Mayuresh Mane, Juan Zurita, Larissa Shenker, Vladimir Ponomarev, Ronald Blasberg
Chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies has shown remarkable responses, but the same level of success has not been observed in solid tumors. A new prostate cancer model (Myc-CaP:PSMA(+)) and a second-generation anti-hPSMA human CAR T cells expressing a Click Beetle Red luciferase reporter) were used to study hPSMA targeting and assess CAR T cell trafficking and persistence by bioluminescence imaging (BLI). We investigated the antitumor efficacy of human CAR T cells targeting human prostate-specific membrane antigen (hPSMA), in the presence and absence of the target antigen; first alone and then combined with a monoclonal antibody targeting the human programmed death receptor 1 (anti-hPD1 mAb)...
March 17, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28345022/ex%C3%A2-vivo-oncolytic-virotherapy-with-myxoma-virus-arms-multiple-allogeneic-bone-marrow-transplant-leukocytes-to-enhance-graft-versus-tumor
#10
Cameron L Lilly, Nancy Y Villa, Ana Lemos de Matos, Haider M Ali, Jess-Karan S Dhillon, Tom Hofland, Masmudur M Rahman, Winnie Chan, Bjarne Bogen, Christopher Cogle, Grant McFadden
Allogeneic stem cell transplant-derived T cells have the potential to seek and eliminate sites of residual cancer that escaped primary therapy. Oncolytic myxoma virus (MYXV) exhibits potent anti-cancer efficacy against human cancers like multiple myeloma (MM) and can arm transplant-derived T cells to become more effective cancer killers in vitro and in an immunodeficient xenotransplant murine model. Here, we tested ex vivo MYXV virotherapy against residual murine MM in immunocompetent mice using an allogeneic mouse-mouse model...
March 17, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28345021/oncolytic-group-b-adenovirus-enadenotucirev-mediates-non-apoptotic-cell-death-with-membrane-disruption-and-release-of-inflammatory-mediators
#11
Arthur Dyer, Ying Di, Hugo Calderon, Sam Illingworth, Gray Kueberuwa, Alison Tedcastle, Phil Jakeman, Suet Lin Chia, Alice Brown, Michael A Silva, David Barlow, John Beadle, Terry Hermiston, David J P Ferguson, Brian Champion, Kerry D Fisher, Leonard W Seymour
Enadenotucirev (EnAd) is a chimeric group B adenovirus isolated by bioselection from a library of adenovirus serotypes. It replicates selectively in and kills a diverse range of carcinoma cells, shows effective anticancer activity in preclinical systems, and is currently undergoing phase I/II clinical trials. EnAd kills cells more quickly than type 5 adenovirus, and speed of cytotoxicity is dose dependent. The EnAd death pathway does not involve p53, is predominantly caspase independent, and appears to involve a rapid fall in cellular ATP...
March 17, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28345020/bacterial-carriers-for-glioblastoma-therapy
#12
Nalini Mehta, Johnathan G Lyon, Ketki Patil, Nassir Mokarram, Christine Kim, Ravi V Bellamkonda
Treatment of aggressive glioblastoma brain tumors is challenging, largely due to diffusion barriers preventing efficient drug dosing to tumors. To overcome these barriers, bacterial carriers that are actively motile and programmed to migrate and localize to tumor zones were designed. These carriers can induce apoptosis via hypoxia-controlled expression of a tumor suppressor protein p53 and a pro-apoptotic drug, Azurin. In a xenograft model of human glioblastoma in rats, bacterial carrier therapy conferred a significant survival benefit with 19% overall long-term survival of >100 days in treated animals relative to a median survival of 26 days in control untreated animals...
March 17, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28054033/augmentation-of-cellular-and-humoral-immune-responses-to-hpv16-and-hpv18-e6-and-e7-antigens-by-vgx-3100
#13
Matthew P Morrow, Kimberly A Kraynyak, Albert J Sylvester, Xuefei Shen, Dinah Amante, Lindsay Sakata, Lamar Parker, Jian Yan, Jean Boyer, Christian Roh, Laurent Humeau, Amir S Khan, Kate Broderick, Kathleen Marcozzi-Pierce, Mary Giffear, Jessica Lee, Cornelia L Trimble, J Joseph Kim, Niranjan Y Sardesai, David B Weiner, Mark L Bagarazzi
We have previously demonstrated the immunogenicity of VGX-3100, a multicomponent DNA immunotherapy for the treatment of Human Papillomavirus (HPV)16/18-positive CIN2/3 in a phase 1 clinical trial. Here, we report on the ability to boost immune responses with an additional dose of VGX-3100. Patients completing our initial phase 1 trial were offered enrollment into a follow on trial consisting of a single boost dose of VGX-3100. Data show both cellular and humoral immune responses could be augmented above pre-boost levels, including the induction of interferon (IFN)γ production, tumor necrosis factor (TNF)α production, CD8+ T cell activation and the synthesis of lytic proteins...
2016: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28035333/reprogramming-antitumor-immunity-against-chemoresistant-ovarian-cancer-by-a-cxcr4-antagonist-armed-viral-oncotherapy
#14
Marcin P Komorowski, Aj Robert McGray, Agnieszka Kolakowska, Kevin Eng, Margaret Gil, Mateusz Opyrchal, Bogumila Litwinska, Michael J Nemeth, Kunle O Odunsi, Danuta Kozbor
Ovarian cancer remains the most lethal gynecologic malignancy owing to late detection, intrinsic and acquired chemoresistance, and remarkable heterogeneity. Here, we explored approaches to inhibit metastatic growth of murine and human ovarian tumor variants resistant to paclitaxel and carboplatin by oncolytic vaccinia virus expressing a CXCR4 antagonist to target the CXCL12 chemokine/CXCR4 receptor signaling axis alone or in combination with doxorubicin. The resistant variants exhibited augmented expression of the hyaluronan receptor CD44 and CXCR4 along with elevated Akt and ERK1/2 activation and displayed an increased susceptibility to viral infection compared with the parental counterparts...
2016: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28035332/poly-functional-and-long-lasting-anticancer-immune-response-elicited-by-a-safe-attenuated-pseudomonas-aeruginosa-vector-for-antigens-delivery
#15
Xavier Chauchet, Dalil Hannani, Sophia Djebali, David Laurin, Benoit Polack, Jacqueline Marvel, Laurent Buffat, Bertrand Toussaint, Audrey Le Gouëllec
Live-attenuated bacterial vectors for antigens delivery have aroused growing interest in the field of cancer immunotherapy. Their potency to stimulate innate immunity and to promote intracellular antigen delivery into antigen-presenting cells could be exploited to elicit a strong and specific cellular immune response against tumor cells. We previously described genetically-modified and attenuated Pseudomonas aeruginosa vectors able to deliver in vivo protein antigens into antigen-presenting cells, through Type 3 secretion system of the bacteria...
2016: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28035331/whole-cell-vaccination-using-immunogenic-cell-death-by-an-oncolytic-adenovirus-is-effective-against-a-colorectal-cancer-model
#16
Tomoki Yamano, Shuji Kubo, Miki Fukumoto, Aya Yano, Yuki Mawatari-Furukawa, Haruki Okamura, Naohiro Tomita
Cancer vaccine application is limited to specific cancer types because few cancer-associated antigens are known to induce tumor rejection. Accordingly, we assessed the utility of Ad881, an oncolytic adenovirus in which viral replication was strictly regulated by the cancer-specific midkine promoter, as a cancer vaccine in a murine colorectal cancer model lacking specific cancer-associated antigens. In CT26 and CMT93 cells, Ad881 (multiplicity of infection: 100 or 1,000) showed stronger cytotoxicity and oncolysis in vitro than its equivalent replication-defective adenovirus, Ad884...
2016: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/27990476/next-frontiers-in-car-t-cell-therapy
#17
EDITORIAL
Christine E Brown, Prasad S Adusumilli
No abstract text is available yet for this article.
2016: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/27933316/systemic-therapy-with-oncolytic-myxoma-virus-cures-established-residual-multiple-myeloma-in-mice
#18
Eric Bartee, Mee Y Bartee, Bjarne Bogen, Xue-Zhong Yu
Multiple myeloma is an incurable malignancy of plasma B-cells. Traditional chemotherapeutic regimes often induce initial tumor regression; however, virtually all patients eventually succumb to relapse caused by either reintroduction of disease during autologous transplant or expansion of chemotherapy resistant minimal residual disease. It has been previously demonstrated that an oncolytic virus known as myxoma can completely prevent myeloma relapse caused by reintroduction of malignant cells during autologous transplant...
2016: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/27933315/immunogenicity-of-self-tumor-associated-proteins-is-enhanced-through-protein-truncation
#19
Tim Kottke, Kevin G Shim, Vanesa Alonso-Camino, Shane Zaidi, Rosa Maria Diaz, Jose Pulido, Jill Thompson, Karishma R Rajani, Laura Evgin, Elizabeth Ilett, Hardev Pandha, Kevin Harrington, Peter Selby, Alan Melcher, Richard Vile
We showed previously that therapy with Vesicular Stomatitis Virus (VSV) expressing tumor-associated proteins eradicates established tumors. We show here that when cellular cDNA were cloned into VSV which retained their own poly-A signal, viral species emerged in culture which had deleted the cellular poly-A signal and also contained a truncated form of the protein coding sequence. Typically, the truncation occurred such that a Tyrosine-encoding codon was converted into a STOP codon. We believe that the truncation of tumor-associated proteins expressed from VSV in this way occurred to preserve the ability of the virus to replicate efficiently...
2016: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/27933314/tunneling-nanotubes-an-alternate-route-for-propagation-of-the-bystander-effect-following-oncolytic-viral-infection
#20
Justin Ady, Venugopal Thayanithy, Kelly Mojica, Phillip Wong, Joshua Carson, Prassanna Rao, Yuman Fong, Emil Lou
Tunneling nanotubes (TNTs) are ultrafine, filamentous actin-based cytoplasmic extensions which form spontaneously to connect cells at short and long-range distances. We have previously described long-range intercellular communication via TNTs connecting mesothelioma cells in vitro and demonstrated TNTs in intact tumors from patients with mesothelioma. Here, we investigate the ability of TNTs to mediate a viral thymidine kinase based bystander effect after oncolytic viral infection and administration of the nucleoside analog ganciclovir...
2016: Molecular Therapy Oncolytics
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