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Oncolytic virus and t cells

Ziye Pan, Jinjiao He, Lubna M Rasoul, Yunye Liu, Ruixiang Che, Yun Ding, Xiaocheng Guo, Jiarui Yang, Dehua Zou, Hua Zhang, Deshan Li, Hongwei Cao
Recombinant Newcastle disease virus (rNDV) is tumor selective and intrinsically oncolytic, which has been developed as a vector to express exogenous genes to enhance its oncolytic efficacy. Our previous studies found that insertion sites of foreign gene in rNDV vector affected its expression and anti-tumor activities. However, the optimal insertion site for foreign genes remains unknown. In this study, we inserted the enhanced green fluorescence protein (EGFP) and IL2 genes into four different intergenic regions of the rNDV using reverse genetics technology...
2016: PloS One
Tianli Xia, Hiroyasu Konno, Glen N Barber
The innate immune regulator STING stimulates cytokine production in response to the presence of cytosolic DNA, which can arise following DNA damage. Extrinsic STING signaling is also needed for antigen-presenting cells (APC) to stimulate antitumor T cell immunity. Here we show that STING signaling is recurrently suppressed in melanoma cells, where this event may enable immune escape after DNA damage. Mechanistically STING signaling was suppressed most frequently by epigenetic silencing of either STING or the cyclic GMP-AMP synthase (cGAS), which generates STING-activating cyclic dinucleotides (CDNs) after binding cytosolic DNA species...
September 28, 2016: Cancer Research
Jayson Hardcastle, Lisa Mills, Courtney S Malo, Fang Jin, Cheyne Kurokawa, Hirosha Geekiyanage, Mark Schroeder, Jann Sarkaria, Aaron J Johnson, Evanthia Galanis
BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor and has a dismal prognosis. Measles virus (MV) therapy of GBM is a promising strategy due to preclinical efficacy, excellent clinical safety, and its ability to evoke antitumor pro-inflammatory responses. We hypothesized that combining anti- programmed cell death protein 1 (anti-PD-1) blockade and MV therapy can overcome immunosuppression and enhance immune effector cell responses against GBM, thus improving therapeutic outcome...
September 23, 2016: Neuro-oncology
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
David F Bauer, Larisa Pereboeva, G Yancey Gillespie, Gretchen A Cloud, Osama Elzafarany, Catherine Langford, James M Markert, Lawrence S Lamb
We designed multimodal tumor vaccine that consists of irradiated tumor cells infected with the oncolytic IL-12-expressing HSV-1 virus, M002. This vaccine was tested against the syngeneic neuroblastoma mouse model Neuro 2a injected into the right caudate nucleus of the immunocompetent A/J mice. Mice were vaccinated via intramuscular injection of multimodal vaccine or uninfected irradiated tumor cells at seven and 14 days after tumor establishment. While there was no survival difference between groups vaccinated with cell-based vaccine applied following tumor injection, a premunition prime/boost vaccination strategy produced a significant survival advantage in both groups and sustained immune response to an intracranial rechallenge of the same tumor...
2016: Journal of Immunology Research
D Kee, G McArthur
Immunotherapy for advanced melanoma has progressed dramatically in the last five years with the approval of immune checkpoint inhibitors targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Inhibition of these targets can break cancer-immune tolerance and result in durable objective responses with significantly improved tolerability over cytokine-based immunotherapy. Ipilimumab is an inhibitor of CTLA-4 and the first-in-class immune checkpoint inhibitor to demonstrate an improvement in overall survival in melanoma...
August 2, 2016: European Journal of Surgical Oncology
Hiroshi Fukuhara, Yasushi Ino, Tomoki Todo
Oncolytic virus therapy is perhaps the next major breakthrough in cancer treatment following the success in immunotherapy using immune checkpoint inhibitors. Oncolytic viruses are defined as genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells without harming the normal tissues. T-Vec (talimogene laherparepvec), a second-generation oncolytic herpes simplex virus type 1 (HSV-1) armed with GM-CSF, was recently approved as the first oncolytic virus drug in the USA and Europe...
August 3, 2016: Cancer Science
Nicholas M Donin, Andrew T Lenis, Stuart Holden, Alexandra Drakaki, Allan Pantuck, Arie Belldegrun, Karim Chamie
PURPOSE: To review the biological mechanisms of action, clinical safety, and efficacy of immunotherapies for urothelial carcinoma (UC). To describe current areas of investigation in immunotherapy, and to highlight ongoing trials and promising investigational agents. MATERIALS AND METHODS: Data was obtained by a search of Pubmed,, and Cochrane databases for English language articles published through February 2016. Applicable abstracts from recent SUO, EAU, AUA, and ASCO meetings were utilized...
July 23, 2016: Journal of Urology
Monika Joshi, Sumanta K Pal, Joseph J Drabick
After decades of disappointments, the use of immunotherapy in cancer has finally come of age and resulted in a real paradigm shift in cancer treatment across many tumor types. With the advent of novel immunotherapies based on increasing understanding of the human immune system, cure has become a real possibility for many patients. The development of cancer vaccines, immune checkpoint inhibitors, chimeric antigen receptor T cell, oncolytic virus based immunotherapy to name a few have given hope to patients. One of the most exciting developments in the era of immunotherapy has been the discovery of checkpoint inhibitors causing blockade of two important immune pathways -- cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death receptor-1 (PD-1), resulting in empowerment of anti-tumor immunity...
June 2016: Discovery Medicine
Di Yu, Justyna Leja-Jarblad, Angelica Loskog, Per Hellman, Valeria Giandomenico, Kjell Oberg, Magnus Essand
Cancer immunotherapy is becoming a cornerstone in the clinical care of cancer patients due to the breakthrough trials with immune checkpoint blockade antibodies and chimeric antigen receptor T cells. The next breakthrough in cancer immunotherapy is likely to be oncolytic viruses engineered to selectively kill tumor cells and deceive the immune system to believe that the tumor is a foreign entity that needs to be eradicated. We have developed AdVince, an oncolytic adenovirus for treatment of liver metastases from neuroendocrine tumor (NET)...
July 21, 2016: Neuroendocrinology
Shengdian Wang, Xiaozhu Li, Pengju Wang, Hang Li, Xuexiang Du, Mingyue Liu, Qibin Huang, Yaohe Wang
: Purpose:Oncolytic adenoviruses (Ad) represent an innovative approach to cancer therapy. Its efficacy depends on multiple actions including direct tumor lysis, stimulation of antiviral and antitumor immune responses. In this study, we investigated the roles of T cell responses in oncolytic adenoviral therapy. EXPERIMENTAL DESIGN: An immunocompetent and viral replication-permissive Syrian hamster tumor model was used. The therapeutic mechanisms of oncolytic Ad were investigated by T-cell deletion, immunohistochemistry staining, and CTL assay...
July 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Tung G Phan, Brigitte Dreno, Antonio Charlys da Costa, Linlin Li, Patricia Orlandi, Xutao Deng, Beatrix Kapusinszky, Juliana Siqueira, Anne-Chantal Knol, Franck Halary, Jacques Dantal, Kathleen A Alexander, Patricia A Pesavento, Eric Delwart
We genetically characterized seven nearly complete genomes in the protoparvovirus genus from the feces of children with diarrhea. The viruses, provisionally named cutaviruses (CutaV), varied by 1-6% nucleotides and shared ~76% and ~82% amino acid identity with the NS1 and VP1 of human bufaviruses, their closest relatives. Using PCR, cutavirus DNA was found in 1.6% (4/245) and 1% (1/100) of diarrhea samples from Brazil and Botswana respectively. In silico analysis of pre-existing metagenomics datasets then revealed closely related parvovirus genomes in skin biopsies from patients with epidermotropic cutaneous T-cell lymphoma (CTCL or mycosis fungoides)...
September 2016: Virology
Ji Young Yoo, Alena C Jaime-Ramirez, Chelsea Bolyard, Hongsheng Dai, Tejaswini Nallanagulagari, Jeffrey Wojton, Brian Hurwitz, Theresa Relation, Jun-Ge Yu, Tae Jin Lee, Michael T Lotze, Jianying Zhang, Carlo M Croce, Jianhua Yu, Michael A Caligiuri, Matthew Old, Balveen Kaur
BACKGROUND: Both the proteasome inhibitor bortezomib and an oncolytic herpes simplex virus-1 (oHSV) expressing GMCSF are currently FDA-approved. While proteasome blockade can increase oHSV replication, immunological consequences and consequent immunotherapy potential are unknown. In this study, we investigated the impact of bortezomib combined with oHSV on tumor cell death and sensitivity to Natural Killier (NK) cell immunotherapy. EXPERIMENTAL DESIGN: Western blot, flow cytometry, and caspase 3/7 activity assays were used to evaluate the induction of apoptosis/autophagy and/or necroptotic cell death...
July 7, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Chrisann Kyi, Michael A Postow
The emergence of immune 'checkpoint inhibitors' such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1) has revolutionized treatment of solid tumors including melanoma, lung cancer, among many others. The goal of checkpoint inhibitor combination therapy is to improve clinical response and minimize toxicities. Rational design of checkpoint combinations considers immune-mediated mechanisms of antitumor activity: immunogenic cell death, antigen release and presentation, activation of T-cell responses, lymphocytic infiltration into tumors and depletion of immunosuppression...
June 2016: Immunotherapy
Ahmad Mohammad Ashshi, Adel Galal El-Shemi, Igor P Dmitriev, Elena A Kashentseva, David T Curiel
BACKGROUND: A major hurdle incurrent to the human clinical application of conditionally replicative adenovirus (CRAd)-based virotherapy agents is their limited therapeutic efficacy. In this study we evaluated whether arming our previously reported Ad5/3Δ24 CRAd vector containing a 24-base pair deletion in the E1A conserved region 2, which allows selective replication within Rb-p16-deficient tumor cells, to express therapeutic genes could improve oncolytic virus potency in ovarian cancer cells...
2016: Journal of Ovarian Research
Zhao-Lun Li, Xuan Liang, He-Cheng Li, Zi-Ming Wang, Tie Chong
AIM: Adenovirus-mediated gene therapy is a novel therapeutic approach for the treatment of cancer, in which replication of the virus itself is the anticancer method. However, the success of this novel therapy is limited due to inefficient delivery of the virus to the target sites. In this study, we used dendritic cells (DCs) as carriers for conditionally replicating adenoviruses (CRAds) in targeting prostate carcinoma (PCa). METHODS: Four types of CRAds, including Ad-PC (without PCa-specific promoter and a recombinant human tumor necrosis factor, rmhTNF, sequence), Ad-PC-rmhTNF (without PCa-specific promoter), Ad-PPC-NCS (without an rmhTNF sequence) and Ad-PPC-rmhTNF, were constructed...
August 2016: Acta Pharmacologica Sinica
Anna E Vilgelm, Douglas B Johnson, Ann Richmond
Immune-checkpoint blockade therapy with antibodies targeting CTLA-4 and PD-1 has revolutionized melanoma treatment by eliciting responses that can be remarkably durable and is now advancing to other malignancies. However, not all patients respond to immune-checkpoint inhibitors. Extensive preclinical evidence suggests that combining immune-checkpoint inhibitors with other anti-cancer treatments can greatly improve the therapeutic benefit. The first clinical success of the combinatorial approach to cancer immunotherapy was demonstrated using a dual-checkpoint blockade with CTLA-4 and PD-1 inhibitors, which resulted in accelerated FDA approval of this therapeutic regimen...
August 2016: Journal of Leukocyte Biology
Akhil Muthigi, Arvin K George, Sam J Brancato, Piyush K Agarwal
Immunotherapy has long played a role in urothelial cancers with the use of bacille Calmette Guérin (BCG) being a mainstay in the treatment of nonmuscle invasive bladder cancer. Novel therapeutic approaches have not significantly impacted mortality in this population and so a renaissance in immunotherapy has resulted. This includes recombinant BCG, oncolytic viruses, monoclonal antibodies, vaccines, and adoptive T-cell therapy. Herein, we provide a review of the current state of the art and future therapies regarding immunotherapeutic strategies for urothelial carcinoma...
June 2016: Therapeutic Advances in Urology
Laure Aurelian, Dominique Bollino, Aric Colunga
Oncolytic viruses (OVs) are an emerging cancer therapeutic, with a near complete absence of serious adverse effects. However, clinical efficacy is relatively modest, related to poor tumor penetration, failure to lyse cancer stem cells (CSCs) and blockade of immunogenic cell death by the immunosuppressive tumor microenvironment. To overcome such limitations, we developed an OV (known as ΔPK) with multimodal anti-tumor activity. ΔPK has potent anti-tumor activity both in melanoma cell lines and xenograft animal models, associated with virus replication and the induction of multiple independent programmed cell death pathways...
July 2016: Pathogens and Disease
Yang Li, Yi-Fei Li, Chong-Zhan Si, Yu-Hui Zhu, Yan Jin, Tong-Tong Zhu, Ming-Yuan Liu, Guang-Yao Liu
Multigene-armed oncolytic adenoviruses are capable of efficiently generating a productive antitumor immune response. The chemokine (C-C motif) ligand 21 (CCL21) binds to CCR7 on naïve T cells and dendritic cells (DCs) to promote their chemoattraction to the tumor and resultant antitumor activity. Interleukin 21 (IL21) promotes survival of naïve T cells while maintaining their CCR7 surface expression, which increases their capacity to transmigrate in response to CCL21 chemoattraction. IL21 is also involved in NK cell differentiation and B cell activation and proliferation...
July 15, 2016: Virus Research
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