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Molecular Therapy Oncolytics

Srinath Rajaraman, Denis Canjuga, Michael Ghosh, Marius Cosmin Codrea, Raika Sieger, Florian Wedekink, Marcos Tatagiba, Marilin Koch, Ulrich M Lauer, Sven Nahnsen, Hans-Georg Rammensee, Michael D Mühlebach, Stefan Stevanovic, Ghazaleh Tabatabai
Glioblastoma is an aggressive primary brain tumor with bad prognosis. On the other hand, oncolytic measles virus (MeV) therapy is an experimental glioma treatment strategy with clinical safety and first evidence of anti-tumoral efficacy. Therefore, we investigated the combination of MeV with conventional therapies by cytotoxic survival assays in long-term glioma cell lines LN229, LNZ308, and glioma stem-like GS8 cells, as well as the basal viral infectivity in primary glioblastoma cultures T81/16, T1094/17, and T708/16...
March 29, 2019: Molecular Therapy Oncolytics
MyLinh T Duong, Matthew R Collinson-Pautz, Eva Morschl, An Lu, Slawomir P Szymanski, Ming Zhang, Mary E Brandt, Wei-Chun Chang, Kelly L Sharp, Steven M Toler, Kevin M Slawin, Aaron E Foster, David M Spencer, J Henri Bayle
Use of chimeric antigen receptors (CARs) as the basis of targeted adoptive T cell therapies has enabled dramatic efficacy against multiple hematopoietic malignancies, but potency against bulky and solid tumors has lagged, potentially due to insufficient CAR-T cell expansion and persistence. To improve CAR-T cell efficacy, we utilized a potent activation switch based on rimiducid-inducible MyD88 and CD40 (iMC)-signaling elements. To offset potential toxicity risks by this enhanced CAR, an orthogonally regulated, rapamycin-induced, caspase-9-based safety switch (iRC9) was developed to allow in vivo elimination of CAR-T cells...
March 29, 2019: Molecular Therapy Oncolytics
Lu Zheng, Nan You, Xiaobing Huang, Huiying Gu, Ke Wu, Na Mi, Jing Li
Previous studies showed that the COpper Metabolism gene MURR1 Domain (COMMD) family of proteins was abnormally expressed in hepatocellular carcinoma (HCC). This study aimed to explore the roles of COMMD1 and COMMD7 in regulating nuclear factor κB (NF-κB) signaling in HCC stem cells (HCSCs). In vivo , the expression of COMMD7 and COMMD1 was determined in 35 pairs of HCC cancer tissues and adjacent tissues, and the effect of COMMD7 silencing on xenograft tumor growth was evaluated. In vitro , the effects of COMMD7 silencing and COMMD1 overexpression on HCSC function were assessed...
March 29, 2019: Molecular Therapy Oncolytics
Cheng-Cao Sun, Shu-Jun Li, Zhen-Long Chen, Guang Li, Qian Zhang, De-Jia Li
Despite advances in early diagnosis and treatment, cancer remains the major reason for mortality worldwide. The Runt-related transcription factor (RUNX) family has been reported to participate in diverse human diseases. However, little is known about their expression and prognostic values in human leukemia. Herein, we conducted a detailed cancer versus normal analysis. The mRNA expression levels of the RUNX family in various kinds of cancers, including leukemia, were analyzed via the ONCOMINE and GEPIA (Gene Expression Profiling Interactive Analysis) databases...
March 29, 2019: Molecular Therapy Oncolytics
Bangxing Hong, Kamaldeen Muili, Chelsea Bolyard, Luke Russell, Tae Jin Lee, Yeshavanth Banasavadi-Siddegowda, Ji Young Yoo, Yuanqing Yan, Leomar Y Ballester, Kurt H Bockhorst, Balveen Kaur
HMGB1 is a ubiquitously expressed intracellular protein that binds DNA and transcription factors and regulates chromosomal structure and function. Under conditions of cell death or stress, it is actively or passively released by cells into the extracellular environment, where it functions as damage-associated molecular pattern (DAMP) that orchestrates pro-inflammatory cytokine release and inflammation. Our results demonstrate that HMGB1 is secreted in the tumor microenvironment after oncolytic HSV (oHSV) infection in vitro and in vivo ...
March 29, 2019: Molecular Therapy Oncolytics
Rachael Mooney, Asma Abdul Majid, Jennifer Batalla-Covello, Diana Machado, Xueli Liu, Joanna Gonzaga, Revathiswari Tirughana, Mohamed Hammad, Maciej S Lesniak, David T Curiel, Karen S Aboody
Oncolytic virotherapy is a promising approach for treating recurrent and/or drug-resistant ovarian cancer. However, its successful application in the clinic has been hampered by rapid immune-mediated clearance or neutralization of the virus, which reduces viral access to tumor foci. To overcome this barrier, patient-derived mesenchymal stem cells have been used to deliver virus to tumors, but variability associated with autologous cell isolations prevents this approach from being broadly clinically applicable...
March 29, 2019: Molecular Therapy Oncolytics
Iris Kemler, Matthew K Ennis, Claudia M Neuhauser, David Dingli
Recombinant measles viruses (MVs) have oncolytic activity against a variety of human cancers. However, their kinetics of spread within tumors has been unexplored. We established an intravital imaging system using the dorsal skin fold chamber, which allows for serial, non-invasive imaging of tumor cells and replication of a fusogenic and a hypofusogenic MV. Hypofusogenic virus-infected cells were detected at the earliest 3 days post-infection (dpi), with peak infection around 6 dpi. In contrast, the fusogenic virus replicated faster: infected cells were detectable 1 dpi and cells were killed quickly...
March 29, 2019: Molecular Therapy Oncolytics
Sant P Chawla, Howard Bruckner, Michael A Morse, Nupur Assudani, Frederick L Hall, Erlinda M Gordon
Rexin-G is a replication-incompetent retroviral vector displaying a cryptic SIG -binding peptide for targeting abnormal Signature ( SIG ) proteins in tumors and encoding a dominant-negative human cyclin G1 construct. Herein we report on the safety and antitumor activity of escalating doses of Rexin-G in gemcitabine-refractory pancreatic adenocarcinoma, with one 10-year survivor. For the safety analysis (n = 20), treatment-related grade 1 adverse events included fatigue (n = 6), chills (n = 2), and headache (n = 1), with no organ damage and no DLT...
March 29, 2019: Molecular Therapy Oncolytics
Chunwei Peng, Guangjie Liu, Kai Huang, Qiang Zheng, Yunsong Li, Changjun Yu
Upregulation of human epididymis protein 4 (HE4) is often observed in different types of cancers, including gastric cancer (GC), but the association of elevated HE4 level with radiation resistance in GC remains unclear. The expression of HE4 and hypoxia-inducible factor 1α subunit (HIF1α) was assessed in GC patient samples and cell lines. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to reveal the regulation between HE4 and HIF1α. Stable HE4 knockdown and HIF1α overexpression were introduced into GC cell lines to study the role of HE4 in the resistance of GC to radiation therapy...
March 29, 2019: Molecular Therapy Oncolytics
Jonathan A Hensel, Vinayak Khattar, Reading Ashton, Selvarangan Ponnazhagan
Carcinoembryonic antigen (CEA) is a human glycoprotein involved in cellular adhesion and expressed during human fetal development. Although expression of CEA largely ceases prior to birth, several human epithelial cancers, including colorectal, gastric, squamous esophageal, and breast carcinomas have been known to overexpress CEA, suggesting its potential as an immunotherapeutic target. Using a transgenic mouse model constitutively expressing human CEA in a spatiotemporal manner as a self-protein and a syngeneic mouse colon cancer cell line, MC38-CEA, overexpressing CEA, we tested the potential of a novel genetic immunotherapy approach against CEA-expressing tumors, using recombinant adeno-associated virus vector encoding CEA (rAAV-CEA) and appropriately timed immune adjuvant application...
March 29, 2019: Molecular Therapy Oncolytics
Michael Karl Melzer, Lisa Zeitlinger, Sabine Mall, Katja Steiger, Roland M Schmid, Oliver Ebert, Angela Krackhardt, Jennifer Altomonte
Vesicular stomatitis virus (VSV) represents an attractive oncolytic virotherapy platform because of its potent tumor cell-killing and immune-stimulating properties; yet the clinical translation of VSV faces numerous challenges, such as inefficient systemic delivery and severe side effects such as neurotoxicity. We hypothesized that we could overcome these limitations and simultaneously enhance the therapy, by combining VSV with adoptively transferred T cell receptor (TCR) transgenic T cells as carrier cells...
March 29, 2019: Molecular Therapy Oncolytics
Ryosuke Uchibori, Takeshi Teruya, Hiroyuki Ido, Ken Ohmine, Yoshihide Sehara, Masashi Urabe, Hiroaki Mizukami, Junichi Mineno, Keiya Ozawa
Adoptive transfer of T cells expressing a chimeric antigen receptor (CAR) is a promising cell-based anticancer therapy. Although clinical studies of this approach show therapeutic efficacy, additional genetic modification is necessary to enhance the efficacy and safety of CAR-T cells. For example, production of an antitumor cytokine from CAR-T cells can potentially enhance their tumor-killing activity, but there are concerns that constitutive expression of anticancer molecules will cause systemic side effects...
March 29, 2019: Molecular Therapy Oncolytics
Feng Xing, Shuo Wang, Jianhong Zhou
Unconventional prefoldin RPB5 interactor (URI, or RMP, a member of the prefoldin family of molecular chaperones) exhibits oncogenic activity in several types of cancer, including ovarian cancer. However, the underlying regulatory mechanism in ovarian cancer remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To elucidate the role of miRNAs in URI-induced ovarian cancer, miR-598 and URI were overexpressed in the SKOV3 ovarian cancer cell line...
March 29, 2019: Molecular Therapy Oncolytics
Hua Zhou, Qian Zhang, Cong Qi
The pathogenesis of endometriosis (EMS) is complicated, and treatment results are unsatisfactory. It has become the focus of gynecological research. Analysis targeting the pathogenesis of EMS is the key to providing more effective treatments. In recent years, the superiority of traditional Chinese medicine in treating EMS has been highlighted, so we investigated the impact of a Chinese medicinal formula (Xiao Liu Fang) on the "3A" ability, in situ , of ectopic endometrial stromal cells in patients with EMS...
March 29, 2019: Molecular Therapy Oncolytics
Haiying Qin, Sneha Ramakrishna, Sang Nguyen, Thomas J Fountaine, Anusha Ponduri, Maryalice Stetler-Stevenson, Constance M Yuan, Waleed Haso, Jack F Shern, Nirali N Shah, Terry J Fry
Despite high remission rates following CAR-T cell therapy in B-ALL, relapse due to loss of the targeted antigen is increasingly recognized as a mechanism of immune escape. We hypothesized that simultaneous targeting of CD19 and CD22 may reduce the likelihood of antigen loss, thus improving sustained remission rates. A systematic approach to the generation of CAR constructs incorporating two target-binding domains led to several novel CD19/CD22 bivalent CAR constructs. Importantly, we demonstrate the challenges associated with the construction of a bivalent CAR format that preserves bifunctionality against both CD19 and CD22...
December 21, 2018: Molecular Therapy Oncolytics
Ahmad Al-Shihabi, Sant P Chawla, Frederick L Hall, Erlinda M Gordon
No abstract text is available yet for this article.
December 21, 2018: Molecular Therapy Oncolytics
Riikka Havunen, João M Santos, Suvi Sorsa, Tommi Rantapero, Dave Lumen, Mikko Siurala, Anu J Airaksinen, Victor Cervera-Carrascon, Siri Tähtinen, Anna Kanerva, Akseli Hemminki
Cancer treatment with local administration of armed oncolytic viruses could potentially induce systemic antitumor effects, or the abscopal effect, as they self-amplify in tumors, induce danger signaling, and promote tumor-associated antigen presentation. In this study, oncolytic adenovirus coding for human tumor necrosis factor alpha (TNF-α) and interleukin-2 (IL-2) Ad5/3-E2F-d24-hTNF-α-IRES-hIL-2 (also known as [a.k.a.] TILT-123) provoked antitumor efficacy in tumors that were injected with Ad5/3-E2F-d24-hTNF-α-IRES-hIL-2 and those that were left non-injected in the same animal...
December 21, 2018: Molecular Therapy Oncolytics
Yu Sakurai, Tomoya Hada, Akari Kato, Yuta Hagino, Wataru Mizumura, Hideyoshi Harashima
Although metastatic cancer is a major cause of death for cancer patients, no efficacious treatment for metastasis is available. We previously showed that the growth of a primary tumor could be inhibited by the administration of an anti-angiogenic small interfering RNA (siRNA) that is encapsulated in an RGD peptide-modified lipid nanoparticle (RGD-LNP). We herein report on the delivery of siRNA by an RGD-LNP to the vasculature is also effective for treating metastatic tumors. We compared the RGD-LNP with the polyethylene glycol (PEG)ylated LNP (PEG-LNP) in terms of accumulation in a lung-metastasized model...
December 21, 2018: Molecular Therapy Oncolytics
Mingjuan Wang, Yanling Hong, Qiang Feng, Xinyan Pan, Shuling Song, Jing Cui, Jin Lei, Hong Fang, Julun Yang
The development of gastric cancer is frequently related to the overexpression of wild-type p21 proteins, but it is rarely related to mutated Ras proteins. We previously constructed a broad-spectrum anti-p21-Ras single-chain variable fragment antibody (scFv), which was carried by the oncolytic adenovirus KGHV500. Here we explored the antitumor effects of this recombinant oncolytic adenovirus carried by cytokine-induced killer (CIK) cells on human gastric SGC7901 cells that overexpress wild-type Ras. The MTT assay, scratch test, Transwell assay, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed in vitro to investigate the proliferation, migration, invasiveness, and cell apoptosis rate, respectively, of the human gastric cell line SGC7901 treated with KGHV500 adenovirus...
December 21, 2018: Molecular Therapy Oncolytics
Pawel Bialk, Yichen Wang, Kelly Banas, Eric B Kmiec
Recent studies point to the evolution of drug resistance in lung cancer as being centered, at least in part, on the upregulation of various genes involved in controlling efflux or drug inactivation. Among the most important of these genes is Nuclear Factor Erythroid 2-Related Factor ( NRF2 ), considered the master regulator of 100-200 target genes involved in cellular responses to oxidative and/or electrophilic stress. With increased focus on the development of combinatorial approaches for cancer treatment, we utilized CRISPR/Cas9 to disable the NRF2 gene in lung cancer cells by disrupting the NRF2 nuclear export signal (NES) domain; phenotypically, the protein is largely blocked from transiting into the nucleus after translation...
December 21, 2018: Molecular Therapy Oncolytics
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