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Cellular Immunotherapy

Kangkang Liu, Erlin Sun, Mingde Lei, Limin Li, Jingda Gao, Xuewu Nian, Lining Wang
Bacillus Calmette-Guerin (BCG) is one of the most effective treatments for bladder cancer. Little attention has been paid to the possible role of neutrophils in BCG immunotherapy. In this study, we examined neutrophil extracellular traps (NETs) formation induced by BCG stimulation, and found that BCG-induced NETs exerted cytotoxicity, induced apoptosis and cell-cycle arrest, and inhibited migration in bladder tumor cells. BCG-activated tumor cells but not non-activated ones elicited NETs formation, in which IL-8 and TNF-α from activated tumor cells both took effect...
February 13, 2019: Clinical Immunology: the Official Journal of the Clinical Immunology Society
William Wheat, Lyndah Chow, Jonathan Coy, Elena Contreras, Michael Lappin, Steven Dow
BACKGROUND: Nonspecific induction of local innate immune responses by mucosally administered immunotherapy is a new approach to protection from upper respiratory tract infections. Therefore, a new liposome-toll-like receptor complex (LTC) immune stimulant was developed and investigated for its ability to activate innate immune responses in cats, both in vitro and in vivo, as part of an initial evaluation of LTC for use as an immunotherapeutic agent in cats. OBJECTIVES: We hypothesized that LTC could activate innate immune responses in cats after topical application to nasal and oropharyngeal mucosal surfaces...
February 15, 2019: Journal of Veterinary Internal Medicine
Mathilde Bonnet, Aurélie Maisonial-Besset, Yingying Zhu, Tiffany Witkowski, Gwenaëlle Roche, Claude Boucheix, Céline Greco, Françoise Degoul
Tetraspanins are exposed at the surface of cellular membranes, which allows for the fixation of cognate antibodies. Developing specific antibodies in conjunction with genetic data would largely contribute to deciphering their biological behavior. In this short review, we summarize the main functions of Tspan8/Co-029 and its role in the biology of tumor cells. Based on data collected from recently reported studies, the possibilities of using antibodies to target Tspan8 in immunotherapy or radioimmunotherapy approaches are also discussed...
February 3, 2019: Cancers
Kevin Dzobo
The human epigenome plays a key role in determining cellular identity and eventually function. Drug discovery undertakings have focused mainly on the role of genomics in carcinogenesis, with the focus turning to the epigenome recently. Drugs targeting DNA and histone modifications are under development with some such as 5-azacytidine, decitabine, vorinostat, and panobinostat already approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This expert review offers a critical analysis of the epigenomics-guided drug discovery and development and the opportunities and challenges for the next decade...
February 2019: Omics: a Journal of Integrative Biology
Hsiling Chiu, Preeti Trisal, Chad Bjorklund, Soraya Carrancio, Estela G Toraño, Carla Guarinos, Despoina Papazoglou, Patrick R Hagner, Asma Beldi-Ferchiou, Karin Tarte, Marie-Hélène Delfau-Larue, Franck Morschhauser, Alan G Ramsay, Anita K Gandhi
Chemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma (FL) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R2 ) has shown clinical synergy in front-line and relapsed/refractory FL. Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer (NK) cells ex vivo from FL patients by enhancing proliferative capacity and T-helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody-dependent cellular cytotoxicity in sensitive and chemo-resistant FL cells, via a cereblon-dependent mechanism...
February 14, 2019: British Journal of Haematology
Marcel P Trefny, Sacha I Rothschild, Franziska Uhlenbrock, Dietmar Rieder, Benjamin Kasenda, Michal A Stanczak, Fiamma Berner, Abhishek S Kashyap, Monika Kaiser, Petra Herzig, Severin Poechtrager, Daniela S Thommen, Florian Geier, Spasenija Savic, Philip Jermann, Ilaria Alborelli, Stefan Schaub, Frank Stenner, Martin Früh, Zlatko Trajanoski, Lukas Flatz, Kirsten D Mertz, Alfred Zippelius, Heinz Läubli
PURPOSE: PD-(L)1 blocking antibodies have clinical activity in metastatic non-small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade.Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells were collected from 35 NSCLC patients receiving nivolumab monotherapy...
February 14, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Lazar Vujanovic, Christopher Chuckran, Yan Lin, Fei Ding, Cindy A Sander, Patricia M Santos, Joel Lohr, Afshin Mashadi-Hossein, Sarah Warren, Andy White, Alan Huang, John M Kirkwood, Lisa H Butterfield
Natural killer (NK) cells are innate cytotoxic and immunoregulatory lymphocytes that have a central role in anti-tumor immunity and play a critical role in mediating cellular immunity in advanced cancer immunotherapies, such as dendritic cell (DC) vaccines. Our group recently tested a novel recombinant adenovirus-transduced autologous DC-based vaccine that simultaneously induces T cell responses against three melanoma-associated antigens for advanced melanoma patients. Here, we examine the impact of this vaccine as well as the subsequent systemic delivery of high-dose interferon-α2b (HDI) on the circulatory NK cell profile in melanoma patients...
2019: Frontiers in Immunology
Ramakrishnan Gopalakrishnan, Hittu Matta, Sunju Choi, Venkatesh Natarajan, Ruben Prins, Songjie Gong, Arta Zenunovic, Nell Narasappa, Fatima Patel, Rekha Prakash, Vishan Chaudhary, Varun Sikri, Saurabh Deepak Chitnis, Andrei Kochegarov, Dan Wang, Magdalena Falat, Michael Kahn, Pooja Smruthi Keerthipati, Naman Sharma, Jyotirmayee Lenka, Tomas Meza Stieben, Jason Braun, Ankita Batra, Katelyn Purvis, Kenta Ito, Jae Han Lee, Alberto Jeronimo, Hannalei Mae Zamora, Allen Membreno, Queenie Qiu, Supriya Peshin, Lalith Namburu, Preet M Chaudhary
Chimeric Antigen Receptor-T (CAR-T) cell immunotherapy has produced dramatic responses in hematologic malignancies. One of the challenges in the field is the lack of a simple assay for the detection of CARs on the surface of immune effector cells. In this study, we describe a novel luciferase-based assay, termed Topanga Assay, for the detection of CAR expression. The assay utilizes a recombinant fusion protein, called Topanga reagent, generated by joining the extra-cellular domain of a CAR-target in frame with one of the marine luciferases or their engineered derivatives...
February 13, 2019: Scientific Reports
Jonathan J Havel, Diego Chowell, Timothy A Chan
Checkpoint inhibitor-based immunotherapies that target cytotoxic T lymphocyte antigen 4 (CTLA4) or the programmed cell death 1 (PD1) pathway have achieved impressive success in the treatment of different cancer types. Yet, only a subset of patients derive clinical benefit. It is thus critical to understand the determinants driving response, resistance and adverse effects. In this Review, we discuss recent work demonstrating that immune checkpoint inhibitor efficacy is affected by a combination of factors involving tumour genomics, host germline genetics, PD1 ligand 1 (PDL1) levels and other features of the tumour microenvironment, as well as the gut microbiome...
February 12, 2019: Nature Reviews. Cancer
Christine N Spencer, Daniel K Wells, Theresa M LaVallee
Immunotherapy results in remarkable clinical benefit in a subset of cancer patients by activating the patient's own immune system. The factors determining which cancer patients will benefit are diverse. Success in realizing precision immunotherapy needs collaboration to bring together multiple diverse data sets. Defining multi-factorial biomarker algorithms for immunotherapy requires new approaches and methodologies that use deep molecular and cellular profiling of the tumor microenvironment, systemic immunity with clinical metadata from clinical trials, and other databases...
February 2019: Trends in Cancer
Manh-Cuong Vo, Thangaraj Jaya Lakshmi, Sung-Hoon Jung, Duck Cho, Hye-Seong Park, Tan-Huy Chu, Hyun-Ju Lee, Hyeoung-Joon Kim, Sang-Ki Kim, Je-Jung Lee
In multiple myeloma (MM), the impaired function of several types of immune cells favors the tumor's escape from immune surveillance and, therefore, its growth and survival. Tremendous improvements have been made in the treatment of MM over the past decade but cellular immunotherapy using dendritic cells, natural killer cells, and genetically engineered T-cells represent a new therapeutic era. The application of these treatments is growing rapidly, based on their capacity to eradicate MM. In this review, we summarize recent progress in cellular immunotherapy for MM and its future prospects...
February 15, 2019: Korean Journal of Internal Medicine
Ikrame Naciri, Marthe Laisné, Laure Ferry, Morgane Bourmaud, Nikhil Gupta, Selene Di Carlo, Anda Huna, Nadine Martin, Lucie Peduto, David Bernard, Olivier Kirsh, Pierre-Antoine Defossez
The proper tissue-specific regulation of gene expression is essential for development and homeostasis in metazoans. However, the illegitimate expression of normally tissue-restricted genes-like testis- or placenta-specific genes-is frequently observed in tumors; this promotes transformation, but also allows immunotherapy. Two important questions are: how is the expression of these genes controlled in healthy cells? And how is this altered in cancer? To address these questions, we used an unbiased approach to test the ability of 350 distinct genetic or epigenetic perturbations to induce the illegitimate expression of over 40 tissue-restricted genes in primary human cells...
February 7, 2019: Nucleic Acids Research
Timon Damelang, Stephen J Rogerson, Stephen J Kent, Amy W Chung
IgG3 comprises only a minor fraction of IgG and has remained relatively understudied until recent years. Key physiochemical characteristics of IgG3 include an elongated hinge region, greater molecular flexibility, extensive polymorphisms, and additional glycosylation sites not present on other IgG subclasses. These characteristics make IgG3 a uniquely potent immunoglobulin, with the potential for triggering effector functions including complement activation, antibody (Ab)-mediated phagocytosis, or Ab-mediated cellular cytotoxicity (ADCC)...
February 8, 2019: Trends in Immunology
Zinaida Good, Luciene Borges, Nora Vivanco Gonzalez, Bita Sahaf, Nikolay Samusik, Robert Tibshirani, Garry P Nolan, Sean C Bendall
Selective differentiation of naive T cells into multipotent T cells is of great interest clinically for the generation of cell-based cancer immunotherapies. Cellular differentiation depends crucially on division state and time. Here we adapt a dye dilution assay for tracking cell proliferative history through mass cytometry and uncouple division, time and regulatory protein expression in single naive human T cells during their activation and expansion in a complex ex vivo milieu. Using 23 markers, we defined groups of proteins controlled predominantly by division state or time and found that undivided cells account for the majority of phenotypic diversity...
February 11, 2019: Nature Biotechnology
Romy E Hoeppli, Anne M Pesenacker
Regulatory T cells (Tregs) are believed to be dysfunctional in autoimmunity. Juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM) result from a loss of normal immune regulation in specific tissues such as joints or muscle and skin, respectively. Here, we discuss recent findings in regard to Treg biology in oligo-/polyarticular JIA and JDM, as well as what we can learn about Treg-related disease mechanism, treatment and biomarkers in JIA/JDM from studies of other diseases. We explore the potential use of Treg immunoregulatory markers and gene signatures as biomarkers for disease course and/or treatment success...
2019: Frontiers in Immunology
Mohammed Alnaggar, Yan Xu, Jingxia Li, Junyi He, Jibing Chen, Man Li, Qingling Wu, Li Lin, Yingqing Liang, Xiaohua Wang, Jiawei Li, Yi Hu, Yan Chen, Kecheng Xu, Yangzhe Wu, Zhinan Yin
BACKGROUND: Cholangiocarcinoma (CCA) is a highly aggressive and fatal tumor. CCA occurs in the epithelial cells of bile ducts. Due to increasing incidences, CCA accounts for 3% of all gastrointestinal malignancies. In addition to comprehensive treatments for cancer, such as surgery, chemotherapy, and radiotherapy, during the past few years, cellular immunotherapy has played an increasingly important role. As a result of our research, we have discovered the γδ T cell-based immunotherapy for CCA...
February 8, 2019: Journal for Immunotherapy of Cancer
Eric W Cross, Trevor J Blain, Divij Mathew, Ross M Kedl
It is common practice for researchers to use antibodies to remove a specific cell type to infer its function. However, it is difficult to completely eliminate a cell type and there is often limited or no information as to how the cells which survive depletion are affected. This is particularly important for CD8+ T cells for two reasons. First, they are more resistant to mAb-mediated depletion than other lymphocytes. Second, targeting either the CD8α or CD8β chain could induce differential effects. We show here that two commonly used mAbs, against either the CD8α or CD8β subunit, can differentially affect cellular metabolism...
2019: PloS One
Abdullah Ladha, Jianzhi Zhao, Elliot M Epner, Jeffrey J Pu
Mantle cell lymphoma is a relatively new recognized hematological malignant disease, comprising of 2.5-6% non-Hodgkin's lymphomas. The complexity of its clinical presentations (nodular pattern, diffuse pattern, and blastoid variant), variety in disease progression, and treatment response, make this disease a research focus to both experimental oncology and clinical oncology. Overexpression of cyclin D1 and chromosome t(11,14) translocation are the known molecular biomarkers of this disease. Mantle cell international prognostic index (MIPI), ki-67 proliferation index, and TP53 mutation are emerging as the prognostic biomarkers...
2019: Experimental Hematology & Oncology
Mariya Lazarova, Alexander Steinle
The immunoreceptor NKG2D belongs to the best-characterised activating receptors of cytotoxic lymphocytes. NKG2D binds to a variety of cell surface glycoproteins distantly related to MHC class I molecules, termed NKG2D ligands (NKG2DL). NKG2DL are inducibly expressed upon cellular stress, viral infection or malignant transformation thus marking "stressed" or "harmful" cells for clearance through NKG2D+ lymphocytes. However, certain viruses and many tumors employ various strategies to escape from NKG2D-mediated immunosurveillance...
February 8, 2019: Expert Opinion on Therapeutic Targets
Cédric Rossi, Pauline Gravelle, Emilie Decaup, Julie Bordenave, Mary Poupot, Marie Tosolini, Don-Marc Franchini, Camille Laurent, Renaud Morin, Jean-Michel Lagarde, Loïc Ysebaert, Laetitia Ligat, Christine Jean, Ariel Savina, Christian Klein, Alba Matas Céspedes, Patricia Perez-Galan, Jean-Jacques Fournié, Christine Bezombes
Follicular lymphoma (FL) is a common non Hodgkin's lymphoma subtype in which immune escape mechanisms are implicated in resistance to chemo-immunotherapy. Although molecular studies point to qualitative and quantitative deregulation of immune checkpoints, in depth cellular analysis of FL immune escape is lacking. Here, by functional assays and in silico analyses we show that a subset of FL patients displays a 'high' immune escape phenotype. These FL cases are characterized by abundant infiltration of PD1+ CD16+ TCRVγ9Vδ2 γδ T lymphocytes...
2019: Oncoimmunology
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