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Molecular Therapy Oncolytics

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
Amit Kumar, Laurie Coquard, Sébastien Pasquereau, Laetitia Russo, Séverine Valmary-Degano, Christophe Borg, Pierre Pothier, Georges Herbein
Although viruses can cause cancer, other studies reported the regression of human tumors upon viral infections. We investigated the cytoreductive potential of human cytomegalovirus (HCMV) in a murine model of human hepatocellular carcinoma (HCC) in severe-immunodeficient mice. Infection of HepG2 cells with HCMV resulted in the absence of tumor or in a limited tumor growth following injection of cells subcutaneously. By contrast all mice injected with uninfected HepG2 cells and with HepG2 cells infected with UV-treated HCMV did develop tumors without any significant restriction...
2016: Molecular Therapy Oncolytics
Challice L Bonifant, Hollie J Jackson, Renier J Brentjens, Kevin J Curran
T cells can be genetically modified to target tumors through the expression of a chimeric antigen receptor (CAR). Most notably, CAR T cells have demonstrated clinical efficacy in hematologic malignancies with more modest responses when targeting solid tumors. However, CAR T cells also have the capacity to elicit expected and unexpected toxicities including: cytokine release syndrome, neurologic toxicity, "on target/off tumor" recognition, and anaphylaxis. Theoretical toxicities including clonal expansion secondary to insertional oncogenesis, graft versus host disease, and off-target antigen recognition have not been clinically evident...
2016: Molecular Therapy Oncolytics
Tina Chang Albershardt, David James Campbell, Andrea Jean Parsons, Megan Merrill Slough, Jan Ter Meulen, Peter Berglund
We have engineered an integration-deficient lentiviral vector, LV305, to deliver the tumor antigen NY-ESO-1 to human dendritic cells in vivo through pseudotyping with a modified Sindbis virus envelop protein. Mice immunized once with LV305 developed strong, dose-dependent, multifunctional, and cytotoxic NY-ESO-1-specific cluster of differentiation 8 (CD8) T cells within 14 days post-immunization and could be boosted with LV305 at least twice to recall peak-level CD8 T-cell responses. Immunization with LV305 protected mice against tumor growth in an NY-ESO-1-expressing CT26 lung metastasis model, with the protective effect abrogated upon depletion of CD8 T cells...
2016: Molecular Therapy Oncolytics
Ruslan Novosiadly, Michael Kalos
Recent clinical data have revealed the remarkable potential for T-cell-modulating agents to induce potent and durable responses in a subset of cancer patients. In this review, we discuss molecular approaches, platforms, and strategies that enable a broader interrogation of the activity of agents that modulate the activity of tumor-specific T cells, to more comprehensively understand how and why the agents succeed and fail, as well as examples of data sets generated in clinical trials that have provided important insights into the biological activity of T-cell therapies and that support further rational development of this exciting treatment modality...
2016: Molecular Therapy Oncolytics
Juan C Corredor, Nicole Redding, Karen Bloté, Stephen M Robbins, Donna L Senger, John C Bell, Paul Beaudry
N-myc oncogene amplification is associated but not present in all cases of high-risk neuroblastoma (NB). Since oncogene expression could often modulate sensitivity to oncolytic viruses, we wanted to examine if N-myc expression status would determine virotherapy efficacy to high-risk NB. We showed that induction of exogenous N-myc in a non-N-myc-amplified cell line background (TET-21N) increased susceptibility to oncolytic vesicular stomatitis virus (mutant VSVΔM51) and alleviated the type I IFN-induced antiviral state...
2016: Molecular Therapy Oncolytics
Mari Hirvinen, Cristian Capasso, Kilian Guse, Mariangela Garofalo, Andrea Vitale, Marko Ahonen, Lukasz Kuryk, Markus Vähä-Koskela, Akseli Hemminki, Vittorio Fortino, Dario Greco, Vincenzo Cerullo
In oncolytic virotherapy, the ability of the virus to activate the immune system is a key attribute with regard to long-term antitumor effects. Vaccinia viruses bear one of the strongest oncolytic activities among all oncolytic viruses. However, its capacity for stimulation of antitumor immunity is not optimal, mainly due to its immunosuppressive nature. To overcome this problem, we developed an oncolytic VV that expresses intracellular pattern recognition receptor DNA-dependent activator of IFN-regulatory factors (DAI) to boost the innate immune system and to activate adaptive immune cells in the tumor...
2016: Molecular Therapy Oncolytics
Pritha Agarwalla, Rajkumar Banerjee
Recent study has shown that N-end rule pathway, an ubiquitin dependent proteolytic system, counteracts cell death by degrading many antisurvival protein fragments like BCLxL, BRCA1, RIPK1, etc. Inhibition of the N-end rule pathway can lead to metabolic stabilization of proapoptotic protein fragments like RIPK1, thereby sensitizing cells to programmed cell death. Receptor interacting serine-threonine protein kinase-1 (RIPK1) is one of the upstream regulators of programmed necrosis known as necroptosis. Necroptosis is particularly gaining attention of cancer biologists as it provides an alternate therapeutic modality to kill cancer cells, which often evolve multiple strategies to circumvent growth inhibition by apoptosis...
2016: Molecular Therapy Oncolytics
Arun Ammayappan, Stephen J Russell, Mark J Federspiel
Mumps virus belongs to the family of Paramyxoviridae and has the potential to be an oncolytic agent. Mumps virus Urabe strain had been tested in the clinical setting as a treatment for human cancer four decades ago in Japan. These clinical studies demonstrated that mumps virus could be a promising cancer therapeutic agent that showed significant antitumor activity against various types of cancers. Since oncolytic virotherapy was not in the limelight until the beginning of the 21(st) century, the interest to pursue mumps virus for cancer treatment slowly faded away...
2016: Molecular Therapy Oncolytics
Demin Jiao, Jian Wang, Wei Lu, Xiali Tang, Jun Chen, Hao Mou, Qing-Yong Chen
The epithelial-mesenchymal transition (EMT) and angiogenesis have emerged as two pivotal events in cancer progression. Curcumin has been extensively studied in preclinical models and clinical trials of cancer prevention due to its favorable toxicity profile. However, the possible involvement of curcumin in the EMT and angiogenesis in lung cancer remains unclear. This study found that curcumin inhibited hepatocyte growth factor (HGF)-induced migration and EMT-related morphological changes in A549 and PC-9 cells...
2016: Molecular Therapy Oncolytics
Matheus Hw Crommentuijn, Rami Kantar, David P Noske, W Peter Vandertop, Christian E Badr, Thomas Würdinger, Casey A Maguire, Bakhos A Tannous
Adeno-associated virus (AAV) vectors expressing tumoricidal genes injected directly into brain tumors have shown some promise, however, invasive tumor cells are relatively unaffected. Systemic injection of AAV9 vectors provides widespread delivery to the brain and potentially the tumor/microenvironment. Here we assessed AAV9 for potential glioblastoma therapy using two different promoters driving the expression of the secreted anti-cancer agent sTRAIL as a transgene model; the ubiquitously active chicken β-actin (CBA) promoter and the neuron-specific enolase (NSE) promoter to restrict expression in brain...
2016: Molecular Therapy Oncolytics
Xiuyan Wang, Isabelle Rivière
The treatment of cancer patients with autologous T cells expressing a chimeric antigen receptor (CAR) is one of the most promising adoptive cellular therapy approaches. Reproducible manufacturing of high-quality, clinical-grade CAR-T cell products is a prerequisite for the wide application of this technology. Product quality needs to be built-in within every step of the manufacturing process. We summarize herein the requirements and logistics to be considered, as well as the state of the art manufacturing platforms available...
2016: Molecular Therapy Oncolytics
Susanne G Warner, Dana Haddad, Joyce Au, Joshua S Carson, Michael P O'Leary, Christina Lewis, Sebastien Monette, Yuman Fong
Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed...
2016: Molecular Therapy Oncolytics
Daniel Abate-Daga, Marco L Davila
T cells genetically targeted with a chimeric antigen receptor (CAR) to B-cell malignancies have demonstrated tremendous clinical outcomes. With the proof in principle for CAR T cells as a therapy for B-cell malignancies being established, current and future research is being focused on adapting CAR technology to other cancers, as well as enhancing its efficacy and/or safety. The modular nature of the CAR, extracellular antigen-binding domain fused to a transmembrane domain and intracellular T-cell signaling domains, allows for optimization by replacement of the various components...
2016: Molecular Therapy Oncolytics
Kheng Newick, Edmund Moon, Steven M Albelda
Chimeric antigen receptor (CAR) T cells are engineered constructs composed of synthetic receptors that direct T cells to surface antigens for subsequent elimination. Many CAR constructs are also manufactured with elements that augment T-cell persistence and activity. To date, CAR T cells have demonstrated tremendous success in eradicating hematological malignancies (e.g., CD19 CARs in leukemias). This success is not yet extrapolated to solid tumors, and the reasons for this are being actively investigated. Here in this mini-review, we discuss some of the key hurdles encountered by CAR T cells in the solid tumor microenvironment...
2016: Molecular Therapy Oncolytics
Dana Haddad, Nicholas Socci, Chun-Hao Chen, Nanhai G Chen, Qian Zhang, Susanne G Carpenter, Arjun Mittra, Aladar A Szalay, Yuman Fong
BACKGROUND: Pancreatic cancer is a fatal disease associated with resistance to conventional therapies. This study aimed to determine changes in gene expression patterns associated with infection and susceptibility of pancreatic cancer cells to an oncolyticvaccinia virus, GLV-1h153, carrying the human sodium iodide symporter for deep tissue imaging of virotherapy. METHODS: Replication and susceptibility of pancreatic adenocarcinoma PANC-1 cells to GLV-1h153 was confirmed with replication and cytotoxicity assays...
2016: Molecular Therapy Oncolytics
Jinxu Fang, Biliang Hu, Si Li, Chupei Zhang, Yarong Liu, Pin Wang
A therapeutically effective cancer vaccine must generate potent antitumor immune responses and be able to overcome tolerance mechanisms mediated by the progressing tumor itself. Previous studies showed that glycoprotein 100 (gp100), tyrosinase-related protein 1 (TRP1), and tyrosinase-related protein 2 (TRP2) are promising immunogens for melanoma immunotherapy. In this study, we administered these three melanoma-associated antigens via lentiviral vectors (termed LV-3Ag) and found that this multi-antigen vaccine strategy markedly increased functional T-cell infiltration into tumors and generated protective and therapeutic antitumor immunity...
2016: Molecular Therapy Oncolytics
Shingo Tsuji, Xuguang Chen, Bryan Hancock, Veronica Hernandez, Barbara Visentin, Katherine Reil, Roger Sabbadini, Matthew Giacalone, W T Godbey
The development of new therapies that can prevent recurrence and progression of nonmuscle invasive bladder cancer remains an unmet clinical need. The continued cost of monitoring and treatment of recurrent disease, along with its high prevalence and incidence rate, is a strain on healthcare economics worldwide. The current work describes the characterization and pharmacological evaluation of VAX-IP as a novel bacterial minicell-based biopharmaceutical agent undergoing development for the treatment of nonmuscle invasive bladder cancer and other oncology indications...
2016: Molecular Therapy Oncolytics
Jan Rh Hanauer, Lisa Gottschlich, Dennis Riehl, Tillmann Rusch, Vivian Koch, Katrin Friedrich, Stefan Hutzler, Steffen Prüfer, Thorsten Friedel, Kay-Martin Hanschmann, Robert C Münch, Christian Jost, Andreas Plückthun, Klaus Cichutek, Christian J Buchholz, Michael D Mühlebach
To target oncolytic measles viruses (MV) to tumors, we exploit the binding specificity of designed ankyrin repeat proteins (DARPins). These DARPin-MVs have high tumor selectivity while maintaining excellent oncolytic potency. Stability, small size, and efficacy of DARPins allowed the generation of MVs simultaneously targeted to tumor marker HER2/neu and cancer stem cell (CSC) marker EpCAM. For optimization, the linker connecting both DARPins was varied in flexibility and length. Flexibility had no impact on fusion helper activity whereas length had...
2016: Molecular Therapy Oncolytics
Marie-Claude Bourgeois-Daigneault, Dominic Guy Roy, Theresa Falls, Kwame Twumasi-Boateng, Lauren Elizabeth St-Germain, Monique Marguerie, Vanessa Garcia, Mohammed Selman, Victoria Ann Jennings, Jessica Pettigrew, Sally Amos, Jean-Simon Diallo, Brad Nelson, John Cameron Bell
Oncolytic viruses are known to stimulate the antitumor immune response by specifically replicating in tumor cells. This is believed to be an important aspect of the durable responses observed in some patients and the field is rapidly moving toward immunotherapy. As a further means to engage the immune system, we engineered a virus, vesicular stomatitis virus (VSV), to encode the proinflammatory cytokine interferon-γ. We used the 4T1 mammary adenocarcinoma as well as other murine tumor models to characterize immune responses in tumor-bearing animals generated by treatment with our viruses...
2016: Molecular Therapy Oncolytics
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