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Oncolytic virus and t cells

Matthew J Atherton, Kyle B Stephenson, Jake K Nikota, Qian N Hu, Andrew Nguyen, Yonghong Wan, Brian D Lichty
Human papilloma virus (HPV)-associated cancer is a significant global health burden and despite the presence of viral transforming antigens within neoplastic cells, therapeutic vaccinations are ineffective for advanced disease. HPV positive TC1 cells are susceptible to viral oncolysis by MG1-E6E7, a custom designed oncolytic Maraba virus. Epitope mapping of mice vaccinated with MG1-E6E7 enabled the rational design of synthetic long peptide (SLP) vaccines against HPV16 and HPV18 antigens. SLPs were able to induce specific CD8+ immune responses and the magnitude of these responses significantly increased when boosted by MG1-E6E7...
March 12, 2018: Vaccine
Dmitriy Zamarin, Jacob M Ricca, Svetlana Sadekova, Anton Oseledchyk, Ying Yu, Wendy M Blumenschein, Jerelyn Wong, Mathieu Gigoux, Taha Merghoub, Jedd D Wolchok
Intralesional therapy with oncolytic viruses (OVs) leads to the activation of local and systemic immune pathways, which may present targets for further combinatorial therapies. Here, we used human tumor histocultures as well as syngeneic tumor models treated with Newcastle disease virus (NDV) to identify a range of immune targets upregulated with OV treatment. Despite tumor infiltration of effector T lymphocytes in response to NDV, there was ongoing inhibition through programmed death ligand 1 (PD-L1), acting as a mechanism of early and late adaptive immune resistance to the type I IFN response and T cell infiltration, respectively...
March 5, 2018: Journal of Clinical Investigation
Michael White, Andrew Freistaedter, Gwendolyn J B Jones, Emmanuel Zervos, Rachel L Roper
Pancreatic cancer is the 5th leading cause of cancer deaths, and there are no effective treatments. We developed a poxvirus platform vaccine with improved immunogenicity and inserted the mesothelin gene to create an anti-mesothelin cancer vaccine. Mesothelin expression is mostly restricted to tumors in adult mammals and thus may be a good target for cancer treatment. We show here that the modified vaccinia virus Ankara (MVA) virus expressing mesothelin and the enhanced MVA virus missing the immunosuppressive A35 gene and expressing mesothelin were both safe in mice and were able to induce IFN-gamma secreting T cells in response to mesothelin expressing tumor cells...
2018: PloS One
Kristian Taipale, Siri Tähtinen, Riikka Havunen, Anniina Koski, Ilkka Liikanen, Päivi Pakarinen, Riitta Koivisto-Korander, Matti Kankainen, Timo Joensuu, Anna Kanerva, Akseli Hemminki
After the landmark approval of T-VEC, oncolytic viruses are finding their way to the clinics. However, response rates have still room for improvement, and unfortunately there are currently no available markers to predict responses for oncolytic immunotherapy. Interleukin 8 (IL-8) production is upregulated in many cancers and it also connects to several pathways that have been shown to impair the efficacy of adenoviral immunotherapy. We studied the role of IL-8 in 103 cancer patients treated with oncolytic adenoviruses...
January 19, 2018: Oncotarget
Tobias Speck, Johannes Pw Heidbuechel, Rūta Veinalde, Dirk Jaeger, Christof von Kalle, Claudia R Ball, Guy Ungerechts, Christine E Engeland
PURPOSE: Immunotherapy with bispecific T cell engagers has achieved striking success against hematological malignancies, but efficacy against solid tumors has been limited. We hypothesized that oncolytic measles viruses encoding bispecific T cell engagers (MV-BiTEs) represent a safe and effective treatment against solid tumors through local BiTE expression, direct tumor cell lysis and in situ tumor vaccination. EXPERIMENTAL DESIGN: To test this hypothesis, we generated MV-BiTEs from the Edmonston B vaccine strain to target two model antigens...
February 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Patrick Lee, Shashi Gujar
The clinical effectiveness of immunotherapies for prostate cancer remains subpar compared with that for other cancers. The goal of most immunotherapies is the activation of immune effectors, such as T cells and natural killer cells, as the presence of these activated mediators positively correlates with patient outcomes. Clinical evidence shows that prostate cancer is immunogenic, accessible to the immune system, and can be targeted by antitumour immune responses. However, owing to the detrimental effects of prostate-cancer-associated immunosuppression, even the newest immunotherapeutic approaches fail to initiate the clinically desired antitumour immune reaction...
February 13, 2018: Nature Reviews. Urology
Frederick F Lang, Charles Conrad, Candelaria Gomez-Manzano, W K Alfred Yung, Raymond Sawaya, Jeffrey S Weinberg, Sujit S Prabhu, Ganesh Rao, Gregory N Fuller, Kenneth D Aldape, Joy Gumin, Luis M Vence, Ignacio Wistuba, Jaime Rodriguez-Canales, Pamela A Villalobos, Clemens M F Dirven, Sonia Tejada, Ricardo D Valle, Marta M Alonso, Brett Ewald, Joanna J Peterkin, Frank Tufaro, Juan Fueyo
Purpose DNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients. Methods A phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A)...
February 12, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Avner Friedman, Xiulan Lai
Oncolytic virus (OV) is a replication competent virus that selectively invades cancer cells; as these cells die under the viral burden, the released virus particles proceed to infect other cancer cells. Oncolytic viruses are designed to also be able to stimulate the anticancer immune response. Thus, one may represent an OV by two parameters: its replication potential and its immunogenicity. In this paper we consider a combination therapy with OV and a checkpoint inhibitor, anti-PD-1. We evaluate the efficacy of the combination therapy in terms of the tumor volume at some later time, for example, 6 months from initial treatment...
2018: PloS One
Frances Collichio, Lauren Burke, Amber Proctor, Diana Wallack, Anthony Collichio, Patricia K Long, David W Ollila
BACKGROUND: Oncolytic viruses are genetically engineered or naturally occurring viruses that selectively replicate in cancer cells without harming normal cells. Talimogene laherparepvec (Imlygic®), the first oncolytic viral therapy approved for treatment of cancer, was approved for treatment of locally advanced melanoma in October 2015. PURPOSE: As a biologic product, use of T. laherparepvec in the clinical setting requires pretreatment planning and a unique systematic approach to deliver the therapy...
February 7, 2018: Annals of Surgical Oncology
Matthias Gromeier, Smita K Nair
Mechanisms to elicit antiviral immunity, a natural host response to viral pathogen challenge, are of eminent relevance to cancer immunotherapy. "Oncolytic" viruses, naturally existing or genetically engineered viral agents with cell type-specific propagation in malignant cells, were ostensibly conceived for their tumor cytotoxic properties. Yet, their true therapeutic value may rest in their ability to provoke antiviral signals that engage antitumor immune responses within the immunosuppressive tumor microenvironment...
January 29, 2018: Annual Review of Medicine
Tiphaine Delaunay, Mathilde Violland, Nicolas Boisgerault, Soizic Dutoit, Virginie Vignard, Christian Münz, Monique Gannage, Brigitte Dréno, Kristine Vaivode, Dace Pjanova, Nathalie Labarrière, Yaohe Wang, E Antonio Chiocca, Fabrice Le Boeuf, John C Bell, Philippe Erbs, Frédéric Tangy, Marc Grégoire, Jean-François Fonteneau
Oncolytic immunotherapy using oncolytic viruses (OV) has been shown to stimulate the antitumor immune response by inducing the release of tumor-associated antigens (TAA) and danger signals from the dying infected tumor cells. In this study, we sought to determine if the lysis of tumor cells induced by different OV: measles virus, vaccinia virus, vesicular stomatitis virus, herpes simplex type I virus, adenovirus or enterovirus, has consequences on the capacity of tumor cells to present TAA, such as NY-ESO-1...
2018: Oncoimmunology
Edmund K Moon, Liang-Chuan S Wang, Kheng Bekdache, Rachel C Lynn, Albert Lo, Stephen H Thorne, Steven M Albelda
T cell trafficking into tumors depends on a "match" between chemokine receptors on effector cells (e.g., CXCR3 and CCR5) and tumor-secreted chemokines. There is often a chemokine/chemokine receptor "mismatch", with tumors producing minute amounts of chemokines, resulting in inefficient targeting of effectors to tumors. We aimed to alter tumors to produce higher levels of CXCL11, a CXCR3 ligand, to attract more effector cells following immunotherapy. Mice bearing established subcutaneous tumors were studied...
2018: Oncoimmunology
Shinya Tada, Masakazu Hamada, Yoshiaki Yura
Oncolytic herpes simplex virus type 1 (HSV-1) strain RH2 induced immunogenic cell death (ICD) with the release and surface exposure of damage-associated molecular patterns (DAMPs) in squamous cell carcinoma (SCC) SCCVII cells. The supernatants of RH2-infected SCCVII cells also exhibited antitumor ability by intratumoral administration in SCCVII tumor-bearing mice. The supernatants of RH2-infected cells and mock-infected cells were concentrated to produce Med24 and MedC for proteomic analyses. In Med24, the up- and down-regulated proteins were observed...
January 23, 2018: Cancers
Julian A Marin-Acevedo, Aixa E Soyano, Bhagirathbhai Dholaria, Keith L Knutson, Yanyan Lou
Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized...
January 12, 2018: Journal of Hematology & Oncology
Jacob P van Vloten, Samuel T Workenhe, Sarah K Wootton, Karen L Mossman, Byram W Bridle
Oncolytic viruses (OVs) are multimodal cancer therapeutics, with one of their dominant mechanisms being in situ vaccination. There is a growing consensus that optimal cancer therapies should generate robust tumor-specific immune responses. Immunogenic cell death (ICD) is a paradigm of cellular demise culminating in the spatiotemporal release of danger-associated molecular patterns that induce potent anticancer immunity. Alongside traditional ICD inducers like anthracycline chemotherapeutics and radiation, OVs have emerged as novel members of this class of therapeutics...
January 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Nikolas T Martin, Christoph Wrede, Julia Niemann, Jennifer Brooks, David Schwarzer, Florian Kühnel, Rita Gerardy-Schahn
Genetic replacement of adenoviral fiber knobs by ligands that enable tumor specific targeting of oncolytic adenoviruses is challenging because the fiber knob contributes to virus assembly. Here, we present a novel concept by describing stable recombinant adenoviruses with tumor specific infection mode. The fiber knob was replaced by endosialidaseNF (endoNF), the tailspike protein of bacteriophage K1F. EndoNF recognizes polysialic acid, an oncofetal antigen characteristic for high malignant tumors of neuroendocrine origin...
December 12, 2017: Biomaterials
Adel Samson, Karen J Scott, David Taggart, Emma J West, Erica Wilson, Gerard J Nuovo, Simon Thomson, Robert Corns, Ryan K Mathew, Martin J Fuller, Timothy J Kottke, Jill M Thompson, Elizabeth J Ilett, Julia V Cockle, Philip van Hille, Gnanamurthy Sivakumar, Euan S Polson, Samantha J Turnbull, Elizabeth S Appleton, Gemma Migneco, Ailsa S Rose, Matthew C Coffey, Deborah A Beirne, Fiona J Collinson, Christy Ralph, D Alan Anthoney, Christopher J Twelves, Andrew J Furness, Sergio A Quezada, Heiko Wurdak, Fiona Errington-Mais, Hardev Pandha, Kevin J Harrington, Peter J Selby, Richard G Vile, Stephen D Griffin, Lucy F Stead, Susan C Short, Alan A Melcher
Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation would up-regulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade...
January 3, 2018: Science Translational Medicine
Richi Nakatake, Masaki Kaibori, Yusuke Nakamura, Yoshito Tanaka, Hideyuki Matushima, Tadayoshi Okumura, Takashi Murakami, Yasushi Ino, Tomoki Todo, Masanori Kon
Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. Oncolytic virus therapy is probably the next major breakthrough in cancer treatment. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 kills tumor cells without damaging the surrounding normal tissues. Here we investigated the antitumor effects of T-01 on HCC and the host's immune response to HCC cells. The cytopathic activities of T-01 were tested in 14 human and one murine hepatoma cell lines in vitro...
December 30, 2017: Cancer Science
Yanhua Gao, Mamdouha A Barmada, Ira Bergman
BACKGROUND: Late metastases develop from cancer of the breast, prostate, lung, kidney and malignant melanomas. Memory T-cells have excellent potential to prevent this devastating development in the same way that they routinely prevent emergence of latent viruses. MATERIAL AND METHODS: A peritoneal tumor mouse model of viral oncotherapy was used to generate therapeutic antitumor memory T-cells. Functional in vivo and in vitro assays were used to study the temporal evolution of their anticancer effects...
January 2018: Anticancer Research
Minah Kim, Maximilian Nitschké, Barbara Sennino, Patrizia Murer, Brian J Schriver, Alexander M Bell, Aishwarya Subramanian, Corry E McDonald, Jiahu Wang, Howard Cha, Marie-Claude Bourgeois-Daigneault, David H Kirn, John C Bell, Naomi De Silva, Caroline J Breitbach, Donald M McDonald
Oncolytic viruses pose many questions in their use in cancer therapy. In this study, we assessed the potential of mpJX-594 (mouse-prototype JX-594), a replication-competent vaccinia virus administered by intravenous injection, to target the tumor vasculature, produce immune activation and tumor cell killing more widespread than the infection, and suppress invasion and metastasis. These actions were examined in RIP-Tag2 transgenic mice with pancreatic neuroendocrine tumors (PNET) that developed spontaneously and progress as in humans...
December 19, 2017: Cancer Research
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