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Cellular Immunotherapy

Christian Peters, Annika Meyer, Léonce Kouakanou, Julia Feder, Tim Schricker, Marcus Lettau, Ottmar Janssen, Daniela Wesch, Dieter Kabelitz
TGF-β is a pleiotropic cytokine with multiple roles in immunity. Apart from its suppressive activity, TGF-β is a driving cytokine in the differentiation of induced regulatory T cells (iTreg) but also in the polarization of interleukin-9 (IL-9) producing T helper 9 (Th9) T cells. Human Vδ2 expressing γδ T cells exert potent cytotoxicity towards a variety of solid tumor and leukemia/lymphoma target cells and thus are in the focus of current strategies to develop cell-based immunotherapies. Here we report that TGF-β unexpectedly augments the cytotoxic effector activity of short-term expanded Vδ2 T cells when purified γδ T cells are activated with specific pyrophosphate antigens and IL-2 or IL-15 in the presence of TGF-β...
2019: Oncoimmunology
Jorieke Weiden, Dion Voerman, Yusuf Dölen, Rajat K Das, Anne van Duffelen, Roel Hammink, Loek J Eggermont, Alan E Rowan, Jurjen Tel, Carl G Figdor
Biomaterial-based scaffolds are promising tools for controlled immunomodulation. They can be applied as three dimensional (3D) culture systems in vitro , whereas in vivo they may be used to dictate cellular localization and exert spatiotemporal control over cues presented to the immune system. As such, scaffolds can be exploited to enhance the efficacy of cancer immunotherapies such as adoptive T cell transfer, in which localization and persistence of tumor-specific T cells dictates treatment outcome. Biomimetic polyisocyanopeptide (PIC) hydrogels are polymeric scaffolds with beneficial characteristics as they display reversible thermally-induced gelation at temperatures above 16°C, which allows for their minimally invasive delivery via injection...
2018: Frontiers in Immunology
Jing Luo, Yang Cheng, Xiao-Yan He, Yi Liu, Na Peng, Zhi-Wei Gong, Kui Wu, Tao Zou
To realize efficiently cellular uptake and enhance the immunostimulation, thiolated cytosine-phosphate-guanine (CpG) oligodeoxynucleotides (ODNs) were self-assembled on hollow gold nanospheres (HGNs) to form CpG-HGNs. The cellular uptake of CpG-HGNs in immune cells was studied in RAW 264.7 cells. Due to the enhanced delivery efficiency, CpG-HGNs exhibited a higher immune stimulatory activity compared with CpG ODNs, resulting in a dramatically enhanced secretion of proinflammatory cytokines. In addition, CpG-HGNs showed low cytotoxicity in RAW 264...
December 3, 2018: Colloids and Surfaces. B, Biointerfaces
S R Chandana, H M Babiker, D Mahadevan
Prognosis remains dismal for pancreatic ductal adenocarcinoma (PDAC). Genomics and proteomics has depicted heterogeneity in PDAC. Collectively, this information could be useful in improving diagnosis, prognosis, modalities of therapy, treatment responses, deciphering drug resistance and new drug development. Areas Covered: We describe major advances in the cellular and molecular subtypes based on next generation sequencing and their predictive and prognostic value in PDAC patients. We review aberrant genes involving in defined cellular processes in PDAC...
December 12, 2018: Expert Opinion on Investigational Drugs
Samis M A Zella, Judith Metzdorf, Emine Ciftci, Friederike Ostendorf, Siegfried Muhlack, Ralf Gold, Lars Tönges
Symptomatic treatment options for Parkinson disease have steadily improved, and individualized therapeutic approaches are becoming established for every stage of the disease. However, disease-modifying therapy with a causal approach is still unavailable. The central causative role of alpha-synuclein pathology, including its progressive spread to most areas of the CNS, has been widely recognized, and a strong involvement of immune responses has recently been discovered. New immunologic technologies have been shown to effectively prevent the progression of alpha-synuclein pathology in animal models...
December 11, 2018: Neurology and Therapy
Chien-Chun Steven Pai, Donald M Simons, Xiaoqing Lu, Michael Evans, Junnian Wei, Yung-Hua Wang, Mingyi Chen, John Huang, Chanhyuk Park, Anthony Chang, Jiaxi Wang, Susan Westmoreland, Christine Beam, Dave Banach, Diana Bowley, Feng Dong, Jane Seagal, Wendy Ritacco, Paul L Richardson, Soumya Mitra, Grace Lynch, Pete Bousquet, John Mankovich, Gillian Kingsbury, Lawrence Fong
While immune checkpoint blockade leads to potent antitumor efficacy, it also leads to immune-related adverse events in cancer patients. These toxicities stem from systemic immune activation resulting in inflammation of multiple organs, including the gastrointestinal tract, lung, and endocrine organs. We developed a dual variable domain immunoglobulin of anti-CTLA4 antibody (anti-CTLA4 DVD, where CTLA4 is defined as cytotoxic T lymphocyte-associated antigen-4) possessing an outer tumor-specific antigen-binding site engineered to shield the inner anti-CTLA4-binding domain...
December 10, 2018: Journal of Clinical Investigation
María E Rodriguez-Ruiz, I Rodriguez, Olwen Leaman, Fernando López Campos, Angel Montero, Antonio J Conde, J J Aristu, Pedro Lara, Manuel Calvo Felipe, Ignacio Melero
Radiotherapy of cancer has been traditionally considered as a local therapy without noticeable effects outside the irradiated fields. However, ionizing radiation exerts multiple biological effects on both malignant and stromal cells that account for a complex spectrum of mechanisms beyond simple termination of cancer cells. In the era of immunotherapy, interest in radiation-induced inflammation and cell death has considerably risen, since these mechanisms lead to profound changes in the systemic immune response against cancer antigens...
December 5, 2018: Pharmacology & Therapeutics
Qianqian Ni, Ngoc B Pham, Wilson S Meng, Guizhi Zhu, Xiaoyuan Chen
Type 1 diabetes mellitus (T1DM) is an autoimmune disease affecting 3 million individuals in the U.S. The pathogenesis of T1DM is driven by immune-mediated destruction of pancreatic β cells, the source of glucose regulator insulin. While T1DM can be successfully managed with insulin replacement therapy, approaches that can modify the underlying immuno-pathology of β cell destruction has been long sought after. Immunotherapy can attenuate T cell responses against β cell antigens. Given the detailed cellular and molecular definitions of T1DM immune responses, rational immunomodulation can be and have been developed in mouse models, and in some instances, tested in humans...
December 6, 2018: Advanced Drug Delivery Reviews
Petra Bacher, Alexander Scheffold
Forkhead box P3-positive regulatory T (Treg) cells are essential mediators of tolerance against self-antigens and harmless exogenous antigens. Treg cell deficiencies result in multiple autoimmune and allergic syndromes in neonates. How Treg cells affect conventional allergies against aeroantigens, which are restricted to a few specific proteins released from inhaled particles, remains controversial. The hallmarks of antigen-specific loss of tolerance are allergen-specific TH 2 cells and IgE. However, difficulties in identifying the rare allergen-specific Treg cells have obscured the cellular basis of tolerance to aeroallergens, which is also a major obstacle for the rational design of novel and more efficient allergen-specific immunotherapies...
December 2018: Journal of Allergy and Clinical Immunology
Gaetano Donofrio, Giulia Tebaldi, Stefania Lanzardo, Roberto Ruiu, Elisabetta Bolli, Andrea Ballatore, Valeria Rolih, Francesca Macchi, Laura Conti, Federica Cavallo
Despite marked advancements in its treatment, breast cancer is still the second leading cause of cancer death in women, due to relapses and distal metastases. Breast cancer stem cells (CSCs), are a cellular reservoir for recurrence, metastatic evolution and disease progression, making the development of novel therapeutics that target CSCs, and thereby inhibit metastases, an urgent need. We have previously demonstrated that the cystine-glutamate antiporter xCT (SLC7A11), a protein that was shown to be overexpressed in mammary CSCs and that plays a key role in the maintenance of their redox balance, self-renewal and resistance to chemotherapy, is a potential target for mammary cancer immunotherapy...
2018: Oncoimmunology
Stephanie M Jensen, Gregory K Potts, Damien B Ready, Melanie J Patterson
Peptides presented by the class-I major histocompatibility complex (MHC-I) are important targets for immunotherapy. The identification of these peptide targets greatly facilitates the generation of T-cell-based therapeutics. Herein, we report the capability of proteolysis targeting chimera (PROTAC) compounds to induce the presentation of specific MHC class-I peptides derived from endogenous cellular proteins. Using LC-MS/MS, we identified several BET-derived MHC-I peptides induced by treatment with three BET-directed PROTAC compounds...
2018: Frontiers in Immunology
Tongjin Wu, Feng Ma, Xiuchang Ma, Weizhe Jia, Enxiang Pan, Genhong Cheng, Ling Chen, Caijun Sun
Persistent inflammation and extensive immune activation have been associated with HIV-1/SIV pathogenesis. Previously, we reported that cholesterol-25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25-HC) had a broad antiviral activity in inhibiting Zika, Ebola, and HIV-1 infection. However, the underlying immunological mechanism of CH25H and 25-HC in inhibiting viral infection remains poorly understood. We report here that 25-HC effectively regulates immune responses for controlling viral infection...
2018: Frontiers in Immunology
Jake S O'Donnell, Michele W L Teng, Mark J Smyth
Anticancer immunotherapies involving the use of immune-checkpoint inhibitors or adoptive cellular transfer have emerged as new therapeutic pillars within oncology. These treatments function by overcoming or relieving tumour-induced immunosuppression, thereby enabling immune-mediated tumour clearance. While often more effective and better tolerated than traditional and targeted therapies, many patients have innate or acquired resistance to immunotherapies. Cancer immunoediting is the process whereby the immune system can both constrain and promote tumour development, which proceeds through three phases termed elimination, equilibrium and escape...
December 6, 2018: Nature Reviews. Clinical Oncology
Tianqun Lang, Yiran Liu, Zhong Zheng, Wei Ran, Yihui Zhai, Qi Yin, Pengcheng Zhang, Yaping Li
Metastatic breast cancer may be resistant to chemo-immunotherapy due to the existence of cancer stem cells (CSC). And the control of particle size and drug release of a drug carrier for multidrug combination is a key issue influencing therapy effect. Here, a cocktail strategy is reported, in which chemotherapy against both bulk tumor cells and CSC and immune checkpoint blockade therapy are intergraded into one drug delivery system. The chemotherapeutic agent paclitaxel (PTX), the anti-CSC agent thioridazine (THZ), and the PD-1/PD-L1 inhibitor HY19991 (HY) are all incorporated into an enzyme/pH dual-sensitive nanoparticle with a micelle-liposome double-layer structure...
December 5, 2018: Advanced Materials
Vardhman Kumar, Shyni Varghese
The emergence of immunotherapies and recent FDA approval of several of them makes them a promising therapeutic strategy for cancer. While these advancements underscore the potential of engaging the immune system to target tumors, this approach has so far been efficient only for certain cancers. Extending immunotherapy as a widely acceptable treatment for various cancers requires a deeper understanding of the interactions of tumor cells within the tumor microenvironment (TME). The immune cells are a key component of the TME, which also includes other stromal cells, soluble factors, and extracellular matrix-based cues...
December 5, 2018: Advanced Healthcare Materials
Mirian Domenech, Julio Sempere, Sara de Miguel, Jose Yuste
The emergence of clinical isolates associated to multidrug resistance is a serious threat worldwide in terms of public health since complicates the success of the antibiotic treatment and the resolution of the infectious process. This is of great concern in pathogens affecting the lower respiratory tract as these infections are one of the major causes of mortality in children and adults. In most cases where the respiratory pathogen is associated to multidrug-resistance, antimicrobial concentrations both in serum and at the site of infection may be insufficient and the resolution of the infection depends on the interaction of the invading pathogen with the host immune response...
2018: Frontiers in Immunology
M P Cavalcanti-Neto, R Q Prado, A R Piñeros, C A Sérgio, T B Bertolini, A F Gembre, S G Ramos, V L Bonato
Given the impossibility to study the lung immune response during Mycobacterium tuberculosis-latent infection, and consequently, the mechanisms that control the bacterial load, it is reasonable to determine the activation of local immunity in the early phase of the infection. The phosphatidylinositol-3-kinase gamma enzyme (PI3Kγ) is involved in the leukocyte recruitment, phagocytosis and cellular differentiation, and therefore, it is considered a promising target for the development of immunotherapies for chronic inflammatory diseases...
December 2018: Tuberculosis
Junaid Raja, Johannes M Ludwig, Scott N Gettinger, Kurt A Schalper, Hyun S Kim
BACKGROUND: Immunotherapy is at the forefront of modern oncologic care. Various novel therapies have targeted all three layers of tumor biology: tumor, niche, and immune system with a range of promising results. One emerging class in both primary and salvage therapy is oncolytic viruses. This therapy offers a multimodal approach to specifically and effectively target and destroy malignant cells, though a barrier oncoviral therapies have faced is a limited therapeutic response to currently delivery techniques...
December 4, 2018: Journal for Immunotherapy of Cancer
Kevin Sek, Christina Mølck, Gregory D Stewart, Lev Kats, Phillip K Darcy, Paul A Beavis
The immune system plays a major role in the surveillance and control of malignant cells, with the presence of tumor infiltrating lymphocytes (TILs) correlating with better patient prognosis in multiple tumor types. The development of 'checkpoint blockade' and adoptive cellular therapy has revolutionized the landscape of cancer treatment and highlights the potential of utilizing the patient's own immune system to eradicate cancer. One mechanism of tumor-mediated immunosuppression that has gained attention as a potential therapeutic target is the purinergic signaling axis, whereby the production of the purine nucleoside adenosine in the tumor microenvironment can potently suppress T and NK cell function...
December 2, 2018: International Journal of Molecular Sciences
Yang Du, Yinhua Jin, Wei Sun, Junjie Fang, Jianjun Zheng, Jie Tian
OBJECTIVES: This review describes the current status and progress of immune checkpoint targets for imaging of malignancies. Immune checkpoint blockade holds great potential for cancer treatment, and clinical implementation into routine is very rapidly progressing. Therefore, it is an urgent need to become familiar with the vocabulary of immunotherapy and with the evaluation of immune checkpoint and related treatments through noninvasive molecular imaging. Currently, immune target-associated imaging mainly includes PET, SPECT, optical imaging, and MRI...
November 30, 2018: European Radiology
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