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Cellular Immunotherapy

Sandro Matosevic
Natural killer (NK) cells are powerful immune effectors whose antitumor activity is regulated through a sophisticated network of activating and inhibitory receptors. As effectors of cancer immunotherapy, NK cells are attractive as they do not attack healthy self-tissues nor do they induce T cell-driven inflammatory cytokine storm, enabling their use as allogeneic adoptive cellular therapies. Clinical responses to adoptive NK-based immunotherapy have been thwarted, however, by the profound immunosuppression induced by the tumor microenvironment, particularly severe in the context of solid tumors...
2018: Journal of Immunology Research
Hiroshi Fujiwara
In cancer immunotherapy, the importance of tumor microenvironment (TME) has recently been highlighted. TME, where trafficked T lymphocytes with tumoricidal activity, particularly endowed by dendritic cells in the sentinel lymph nodes, suppress cancer cells, consists of multiple cellular components, such as fibroblasts, macrophages, myeloid-derived suppressor cells, monocytes, neutrophils, regulatory T cells, and NK cells, and non-cellular components, such as extracellular matrix and blood and lymphatic vessels...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Kathrin Rothfelder, Ilona Hagelstein, Malte Roerden, Gunnar Blumenstock, Martin Hofmann, Tina Nuebling, Gundram Jung, Helmut Rainer Salih, Daniela Dörfel
OX40 and its ligand are members of the TNF/TNF receptor superfamily, which includes various molecules influencing cellular signaling and function of both tumor and immune cells. The ability of OX40 to promote proliferation and differentiation of activated T cells fueled present attempts to modulate this immune checkpoint to reinforce antitumor immunity. While we recently found evidence for the involvement of OX40 in pathophysiology of acute myeloid leukemia including natural killer (NK) cell immunosurveillance, less is known on its role in acute lymphoblastic leukemia (ALL)...
October 6, 2018: Neoplasia: An International Journal for Oncology Research
Xavier Thomas, Etienne Paubelle
Cellular immunotherapy with autologous or allogeneic T cells, genetically engineered to express chimeric antigen receptors (CARs) or T-cell receptors, in order to redirect their cytotoxic specificity toward malignant cells, is emerging as a promising new treatment modality. The most advanced approach in clinical development is the use of anti-CD19 CAR T-cells for the treatment of CD19+ B-cell malignancies, including acute lymphocytic leukemia (ALL). Areas covered: Recently, the Food and Drug Administration (FDA) approved the first anti-CD19 CAR T-cell product, tisagenlecleucel, for the treatment of pediatric and young adult patients with relapsed/refractory ALL...
October 8, 2018: Expert Opinion on Biological Therapy
Josef Finsterer, Stephan Iglseder, Julia Wanschitz, Raffi Topakian, Wolfgang N Löscher, Wolfgang Grisold
Hereditary transthyretin(TTR)-related amyloidosis (ATTRm amyloidosis) is an endemic/non-endemic, autosomal-dominant, early- and late-onset, rare, progressive disorder, predominantly manifesting as length-dependent, small-fiber dominant, axonal polyneuropathy and frequently associated with cardiac disorders and other multisystem diseases. ATTRm amyloidosis is due to variants in the TTR gene, with the substitution Val30Met as the most frequent mutation. TTR mutations lead to destabilisation and dissociation of TTR tetramers into variant TTR monomers, and formation of amyloid fibrils, which are consecutively deposited extra-cellularly in various tissues, such as nerves, heart, brain, eyes, intestines, kidneys...
October 8, 2018: Acta Neurologica Scandinavica
Sang-Soo Kim, Joe B Harford, Manish Moghe, Antonina Rait, Esther H Chang
The tumor suppressor p53 responds to genotoxic and oncogenic stresses by inducing cell cycle arrest and apoptosis. Recent studies suggest that p53 also participates in the regulation of cellular immune responses. Here, we have investigated the potential of p53 gene therapy to augment immune checkpoint inhibition by combining an anti-programmed cell death protein 1 (PD1) antibody with SGT-53, our investigational nanomedicine carrying a plasmid encoding human wild-type p53. In three syngeneic mouse tumor models examined including a breast cancer, a non-small cell lung carcinoma, and a glioblastoma, SGT-53 sensitized otherwise refractory tumors to anti-PD1 antibody...
2018: Oncoimmunology
Adrian C Bateman
This mini review describes some of the key interactions between cancer cells and the immune system. This includes the concept of tumour cell immunosurveillance, mechanisms of immune evasion by tumour cells and some of the novel immunology-based anticancer therapies that have recently been introduced. The latter are also set into the context of the enlarging spectrum of immunohistochemistry-based and molecular testing that can now be performed on formalin-fixed and paraffin-embedded tissues for predicting response to both well-established and newly developed agents...
October 1, 2018: Journal of Clinical Pathology
Robert B Vernon, Michel D Gooden, Anton Preisinger, John A Gebe
Immunomodulatory monoclonal antibodies (IM-mAbs) are a cornerstone of modern immunotherapy; however, when administered systemically (i.e., via injection), these agents can generate a variety of negative side effects. For many diseases, systemic delivery of IM-mAbs is the most effective mode of treatment, but in instances where the cellular target occupies a limited, well-defined space (e.g., solid tumors or cellularized implants) local, controlled release of IM-mAbs might be desirable. Antibodies are highly sensitive to a variety of environmental conditions, which limit the kinds of polymers suitable for antibody retention and controlled release...
December 1, 2018: Materials Science & Engineering. C, Materials for Biological Applications
Michael Erdmann, Ugur Uslu, Manuel Wiesinger, Mareke Brüning, Tobias Altmann, Erwin Strasser, Gerold Schuler, Beatrice Schuler-Thurner
Dendritic cell (DC)-based vaccines have been successfully used for immunotherapy of cancer and infections. A major obstacle is the need for high-level class A cleanroom cGMP facilities for DC generation. The CliniMACS Prodigy® (Prodigy) represents a new platform integrating all GMP-compliant manufacturing steps in a closed system for automated production of various cellular products, notably T cells, NK cells and CD34+ cells. We now systematically tested its suitability for producing human mature monocyte-derived DCs (Mo-DCs), and optimized it by directly comparing the Prodigy approach to our established standard production of Mo-DCs from elutriated monocytes in dishes or bags...
September 25, 2018: Journal of Immunological Methods
Jian Li, Ding Qiu, Yuqing Liu, Jian Xiong, Ying Wang, Xia Yang, Xiaolan Fu, Lixing Zheng, Gaoxing Luo, Malcolm M Q Xing, Yuzhang Wu
While there has been extensive development of soluble epitope-specific peptides to induce immune tolerance for the treatment of autoimmune diseases, the clinical efficacy of soluble peptides-based immunotherapy was still uncertain. Recent strategies to develop antigen carriers coupled with peptides have shown promise results in preclinical animal models. Here we developed functional amphiphilic hyperbranched polymers with different grafting degrees of hydrophobic chains as antigen MOG peptide carriers and evaluated their ability to induce immune tolerance...
September 28, 2018: ACS Nano
John W Hickey, Alyssa K Kosmides, Jonathan P Schneck
T cells are crucial contributors to mounting an effective immune response and increasingly the focus of therapeutic interventions in cancer, infectious disease, and autoimmunity. Translation of current T cell immunotherapies has been hindered by off-target toxicities, limited efficacy, biological variability, and high costs. As T cell therapeutics continue to develop, the application of engineering concepts to control their delivery and presentation will be critical for their success. Here, we outline the engineer's toolbox and contextualize it with the biology of T cells...
2018: International Review of Cell and Molecular Biology
Kishore Kumar Jella, Tahseen H Nasti, Zhentian Li, Sudarshan R Malla, Zachary S Buchwald, Mohammad K Khan
Exosomes are extracellular vesicles ranging from 30 to 150 nm in diameter that contain molecular constituents of their host cells. They are released from different types of cells ranging from immune to tumor cells and play an important role in intercellular communication. Exosomes can be manipulated by altering their host cells and can be loaded with products of interest such as specific drugs, proteins, DNA and RNA species. Due to their small size and the unique composition of their lipid bilayer, exosomes are capable of reaching different cell types where they alter the pathophysiological conditions of the recipient cells...
September 26, 2018: Vaccines
Xiaoxuan Zhao, Yuepeng Jiang, Lin Wang, Zhihao Li, Qiang Li, Xiaoling Feng
Recurrent spontaneous abortion is a global problem, and unexplained recurrent abortion triggered by immunological factors is an important focus of current research. Helper T lymphocytes (Th cells) and regulatory T lymphocytes (Treg cells) are central in human immune regulation and play a complex role in pregnancy. Natural killer cells (NK cells) exist in the endometrium and cooperate with T lymphocytes to create immune tolerance at the maternal-fetal interface, which is essential for successful pregnancy. This review has analyzed studies on Th17 cell, Treg cell and NK cell dysfunction and cellular imbalances which may contribute to unexplained recurrent spontaneous abortion to suggest a possible direction for future immunotherapies...
July 2018: Geburtshilfe und Frauenheilkunde
Maik Luu, Katharina Weigand, Fatana Wedi, Carina Breidenbend, Hanna Leister, Sabine Pautz, Till Adhikary, Alexander Visekruna
The gut microbiota produces metabolites such as short-chain fatty acids (SCFAs) that regulate the energy homeostasis and impact on immune cell function of the host. Recently, innovative approaches based on the oral administration of SCFAs have been discussed for therapeutic modification of inflammatory immune responses in autoimmune diseases. So far, most studies have investigated the SCFA-mediated effects on CD4+ T cells and antigen presenting cells. Here we show that butyrate and, to a lesser degree, propionate directly modulate the gene expression of CD8+ cytotoxic T lymphocytes (CTLs) and Tc17 cells...
September 26, 2018: Scientific Reports
Ming-Huan Mao, Hai-Bo Huang, Xi-Ling Zhang, Kai Li, Yi-Li Liu, Ping Wang
BACKGROUND: As an inorganic compound used to treat various cancers and other diseases, arsenic trioxide (As2 O3 ) has been reported to induce cellular apoptosis in certain kinds of cancers including bladder cancer. The aim of the present study was to elucidate the crucial cooperative role of As2 O3 and intravesical bacillus Calmette-Guerin (BCG) immunotherapy and its ability to protect against bladder cancer by targeting the IER3/Nrf2 pathway. METHOD: Initially, an orthotopic bladder cancer model was established in mice by means of intravesical instillation of the human bladder cancer cell line 5637...
November 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Cleo Goyvaerts, Karine Breckpot
Dendritic cells (DCs) are recognized as highly potent antigen-presenting cells that are able to stimulate cytotoxic T lymphocyte (CTL) responses with antitumor activity. Consequently, DCs have been explored as cellular vaccines in cancer immunotherapy. To that end, DCs are modified with tumor antigens to enable presentation of antigen-derived peptides to CTLs. In this review we discuss the use of viral vectors for in situ modification of DCs, focusing on their clinical applications as anticancer vaccines. Among the viral vectors discussed are those derived from viruses belonging to the families of the Poxviridae, Adenoviridae, Retroviridae, Togaviridae, Paramyxoviridae , and Rhabdoviridae ...
2018: Frontiers in Immunology
Frederick S Varn, Evelien Schaafsma, Yue Wang, Chao Cheng
Viruses affect approximately 20% of all human cancers and induce expression of immunogenic viral oncoproteins that make these tumors potent targets for immune checkpoint inhibitors. In this study, we apply computational tools to The Cancer Genome Atlas and other genomic datasets to define how virus infection shapes the tumor immune microenvironment and genetic architecture of 6 virus-associated tumor types. Across cancers, the cellular composition of the microenvironment varied by viral status, with virus-positive tumors often exhibiting increased infiltration of cytolytic cell types compared to their virus-negative counterparts...
September 25, 2018: Cancer Research
K G Paulson, V Voillet, M S McAfee, D S Hunter, F D Wagener, M Perdicchio, W J Valente, S J Koelle, C D Church, N Vandeven, H Thomas, A G Colunga, J G Iyer, C Yee, R Kulikauskas, D M Koelle, R H Pierce, J H Bielas, P D Greenberg, S Bhatia, R Gottardo, P Nghiem, A G Chapuis
Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors...
September 24, 2018: Nature Communications
Charu Aggarwal, Roger B Cohen, Matthew P Morrow, Kimberly A Kraynak, Albert J Sylvester, Dawson M Knoblock, Joshua Bauml, Gregory S Weinstein, Alexander Lin, Jean Boyer, Lindsay Sakata, Sophie Tan, Aubrey Anton, Kelsie Dickerson, Drishty Mangrolia, Russell Vang, Michael Dallas, Sandra Oyola, Susan Duff, Mark T Esser, Rakesh Kumar, David B Weiner, Ildiko Csiki, Mark Bagarazzi
PURPOSE: Clinical responses with programmed death (PD-1) receptor directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18 are attractive targets for therapeutic immunization, and offer an immune activation strategy that may be complementary to PD-1 inhibition. EXPERIMENTAL DESIGN: We report Phase Ib/II safety, tolerability and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL-12 encoding plasmids) delivered by electroporation with CELLECTRA® constant current device...
September 21, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Mohammad Ali Amini, Azhar Z Abbasi, Ping Cai, HoYin Lip, Claudia R Gordijo, Jason Li, Branson Chen, Li Zhang, Andrew M Rauth, Xiao Yu Wu
Background: Tumor microenvironment (TME) and associated multiple factors are found to contribute to the failures in cancer therapies, including chemo- and immunotherapy. Here we report a new multimodal strategy that uses a bioreactive multifunctional hybrid polymer-lipid encapsulated manganese dioxide nanoparticle (PLMD NP) system to remodel the TME, suppress drug resistance factors, reverse immunosuppressive conditions, and enhance chemotherapy efficacy. Methods: The influence of PLMD NPs on enhancing cellular uptake in EMT6 mouse breast cancer cells and tumor penetration of doxorubicin (DOX) in EMT6 orthotopic breast tumor mouse model was evaluated using confocal microscopy (n = 3-4)...
September 14, 2018: Journal of the National Cancer Institute
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