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Adoptive T cell therapy

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https://www.readbyqxmd.com/read/28818060/rna-transfection-of-%C3%AE-%C3%AE-t-cells-with-a-chimeric-antigen-receptor-or-an-%C3%AE-%C3%AE-t-cell-receptor-a-safer-alternative-to-genetically-engineered-%C3%AE-%C3%AE-t-cells-for-the-immunotherapy-of-melanoma
#1
Dennis C Harrer, Bianca Simon, Shin-Ichiro Fujii, Kanako Shimizu, Ugur Uslu, Gerold Schuler, Kerstin F Gerer, Stefanie Hoyer, Jan Dörrie, Niels Schaft
BACKGROUND: Adoptive T-cell therapy relying on conventional T cells transduced with T-cell receptors (TCRs) or chimeric antigen receptors (CARs) has caused substantial tumor regression in several clinical trials. However, genetically engineered T cells have been associated with serious side-effects due to off-target toxicities and massive cytokine release. To obviate these concerns, we established a protocol adaptable to GMP to expand and transiently transfect γ/δ T cells with mRNA...
August 17, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28810803/driving-cars-on-the-highway-to-solid-cancer-some-considerations-on-the-adoptive-therapy-with-car-t-cells
#2
Hinrich Abken
Adoptive therapy with chimeric antigen receptor (CAR) redirected T cells achieved lasting remissions in hematologic malignancies even in terminal stages of the disease; exploring CAR T cell therapy in the treatment of solid tumors has just begun, balancing efficacy versus toxicity in early phase trials. In contrast to leukemia/lymphoma, solid tumors display a tremendously variable biology demanding different strategies to make a T cell attack successful in the long-term. We summarize current developments, discuss the hurdles and consider some modifications to improve the CAR T cell therapy in the treatment of solid tumors...
August 16, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28809608/treatment-of-patients-with-metastatic-cancer-using-a-major-histocompatibility-complex-class-ii-restricted-t-cell-receptor-targeting-the-cancer-germline-antigen-mage-a3
#3
Yong-Chen Lu, Linda L Parker, Tangying Lu, Zhili Zheng, Mary Ann Toomey, Donald E White, Xin Yao, Yong F Li, Paul F Robbins, Steven A Feldman, Pierre van der Bruggen, Christopher A Klebanoff, Stephanie L Goff, Richard M Sherry, Udai S Kammula, James C Yang, Steven A Rosenberg
Purpose Adoptive transfer of genetically modified T cells is being explored as a treatment for patients with metastatic cancer. Most current strategies use genes that encode major histocompatibility complex (MHC) class I-restricted T-cell receptors (TCRs) or chimeric antigen receptors to genetically modify CD8(+) T cells or bulk T cells for treatment. Here, we evaluated the safety and efficacy of an adoptive CD4(+) T-cell therapy using an MHC class II-restricted, HLA-DPB1*0401-restricted TCR that recognized the cancer germline antigen, MAGE-A3 (melanoma-associated antigen-A3)...
August 15, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28804488/anti-adhesion-therapies-in-inflammatory-bowel-disease-molecular-and-clinical-aspects
#4
REVIEW
Sebastian Zundler, Emily Becker, Carl Weidinger, Britta Siegmund
The number of biologicals for the therapy of immunologically mediated diseases is constantly growing. In contrast to other agents that were previously introduced in rheumatologic or dermatologic diseases and only later adopted for the treatment of inflammatory bowel diseases (IBDs), the field of IBD was ground breaking for the concept of anti-adhesion blockade. Anti-adhesion antibodies selectively target integrins controlling cell homing to the intestine, which leads to reduction of inflammatory infiltration to the gut in chronic intestinal inflammation...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28801306/inducible-activation-of-myd88-and-cd40-in-car-t-cells-results-in-controllable-and-potent-antitumor-activity-in-preclinical-solid-tumor-models
#5
Melinda Mata, Claudia Gerken, Phuong Nguyen, Giedre Krenciute, David M Spencer, Stephen Gottschalk
Adoptive immunotherapy with T-cells expressing chimeric antigen receptors (CARs) has had limited success for solid tumors in early phase clinical studies. We reasoned that introducing into CAR T-cells an inducible co-stimulatory (iCO) molecule consisting of a chemical inducer of dimerization (CID)-binding domain and the MyD88 and CD40 signaling domains would improve and control CAR T-cell activation. In the presence of CID, T-cells expressing HER2-CARζ and a MyD88/CD40-based iCO molecule (HER2ζ.iCO T-cells) had superior T-cell proliferation, cytokine production, and ability to sequentially kill targets in vitro relative to HER2ζ...
August 11, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28794626/folic-acid-functionalized-polyethylenimine-superparamagnetic-iron-oxide-nanoparticles-as-theranostic-agents-for-magnetic-resonance-imaging-and-pd-l1-sirna-delivery-for-gastric-cancer
#6
Xin Luo, Xia Peng, Jingying Hou, Shuyun Wu, Jun Shen, Lingyun Wang
Programmed death ligand-1 (PD-L1), which is highly expressed in gastric cancers, interacts with programmed death-1 (PD-1) on T cells and is involved in T-cell immune resistance. To increase the therapeutic safety and accuracy of PD-1/PD-L1 blockade, RNA interference through targeted gene delivery was performed in our study. We developed folic acid (FA)- and disulfide (SS)-polyethylene glycol (PEG)-conjugated polyethylenimine (PEI) complexed with superparamagnetic iron oxide Fe3O4 nanoparticles (SPIONs) as a siRNA-delivery system for PD-L1 knockdown...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28792537/isolation-and-functional-characterization-of-hepatitis-b-virus-specific-t-cell-receptors-as-new-tools-for-experimental-and-clinical-use
#7
Karin Wisskirchen, Kai Metzger, Sophia Schreiber, Theresa Asen, Luise Weigand, Christina Dargel, Klaus Witter, Elisa Kieback, Martin F Sprinzl, Wolfgang Uckert, Matthias Schiemann, Dirk H Busch, Angela M Krackhardt, Ulrike Protzer
T-cell therapy of chronic hepatitis B is a novel approach to restore antiviral T-cell immunity and cure the infection. We aimed at identifying T-cell receptors (TCR) with high functional avidity that have the potential to be used for adoptive T-cell therapy. To this end, we cloned HLA-A*02-restricted, hepatitis B virus (HBV)-specific T cells from patients with acute or resolved HBV infection. We isolated 11 envelope- or core-specific TCRs and evaluated them in comprehensive functional analyses. T cells were genetically modified by retroviral transduction to express HBV-specific TCRs...
2017: PloS One
https://www.readbyqxmd.com/read/28791124/combining-dendritic-cells-and-b-cells-for-presentation-of-oxidised-tumour-antigens-to-cd8-t-cells
#8
Melanie L Grant, Nicholas Shields, Silke Neumann, Katrin Kramer, Andrea Bonato, Christopher Jackson, Margaret A Baird, Sarah L Young
The dendritic cell (DC) is the foremost antigen-presenting cell (APC) for ex vivo expansion of tumour-specific patient T cells. Despite marked responses in some patients following reinfusion of DC-activated autologous or HLA-matched donor T cells, overall response rates remain modest in solid tumours. Furthermore, most studies aim to generate immune responses against defined tumour-associated antigens (TAA), however, meta-analysis reveals that those approaches have less clinical success than those using whole tumour cells or their components...
July 2017: Clinical & Translational Immunology
https://www.readbyqxmd.com/read/28783722/identification-of-essential-genes-for-cancer-immunotherapy
#9
Shashank J Patel, Neville E Sanjana, Rigel J Kishton, Arash Eidizadeh, Suman K Vodnala, Maggie Cam, Jared J Gartner, Li Jia, Seth M Steinberg, Tori N Yamamoto, Anand S Merchant, Gautam U Mehta, Anna Chichura, Ophir Shalem, Eric Tran, Robert Eil, Madhusudhanan Sukumar, Eva Perez Guijarro, Chi-Ping Day, Paul Robbins, Steve Feldman, Glenn Merlino, Feng Zhang, Nicholas P Restifo
Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic loss-of-function mutations involved in resistance to these therapies, by using a genome-scale CRISPR-Cas9 library that consisted of around 123,000 single-guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8(+) T cells. The genes that were most enriched in the screen have key roles in antigen presentation and interferon-γ signalling, and correlate with cytolytic activity in patient tumours from The Cancer Genome Atlas...
August 7, 2017: Nature
https://www.readbyqxmd.com/read/28781967/immunotherapeutic-strategies-for-gastric-carcinoma-a-review-of-preclinical-and-clinical-recent-development
#10
REVIEW
Mohamed Abozeid, Antonio Rosato, Roberta Sommaggio
Gastric carcinoma (GC) is the 2nd most common cause of cancer-related death. Despite advances in conventional treatment and surgical interventions, a high percentage of GC patients still have poor survival. Recently, immunotherapy has become a promising approach to treat GC. Here, we present preclinical and clinical studies encouraging the use of vaccination, adoptive T-cell therapy (ACT), and immune checkpoint inhibitors, such as programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28771103/overcoming-barriers-of-car-t-cell-therapy-in-patients-with-mesothelin-expressing-cancers
#11
Mark H O'Hara, Caitlin Stashwick, Gabriela Plesa, Janos L Tanyi
One obstacle to the application of immunotherapy to solid malignancies is to overcome the existing tolerance to self-antigens. Vaccine strategies aimed at harnessing endogenous antitumor T cells are limited by the T-cell receptor repertoire, which can be detected within the thymus as central tolerance or rendered nonfunctional by post-thymic mechanisms of peripheral tolerance. Adoptive immunotherapy can overcome these obstacles, since therapeutically effective T cells can be engineered to recognize tumors. Continued advancements in novel treatments, including immunotherapy, in solid malignancies are imperative...
August 3, 2017: Immunotherapy
https://www.readbyqxmd.com/read/28769930/anti-interleukin-6-promotes-allogeneic-bone-marrow-engraftment-and-prolonged-graft-survival-in-an-irradiation-free-murine-transplant-model
#12
Nicolas Granofszky, Andreas M Farkas, Moritz Muckenhuber, Benedikt Mahr, Lukas Unger, Svenja Maschke, Nina Pilat, Raimund Holly, Mario Wiletel, Heinz Regele, Thomas Wekerle
Transfer of recipient regulatory T cells (Tregs) induces mixed chimerism and tolerance in an irradiation-free bone marrow (BM) transplantation (BMT) model involving short-course co-stimulation blockade and mTOR inhibition. Boosting endogenous Tregs pharmacologically in vivo would be an attractive alternative avoiding the current limitations of performing adoptive cell therapy in the routine clinical setting. Interleukin-6 (IL-6) potently inhibits Treg differentiation and its blockade was shown to increase Treg numbers in vivo...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28768648/c-c-chemokine-receptor-type-5-ccr5-mediated-docking-of-transferred-tregs-protects-against-early-blood-brain-barrier-disruption-after-stroke
#13
Peiying Li, Long Wang, Yuxi Zhou, Yu Gan, Wen Zhu, Yuguo Xia, Xiaoyan Jiang, Simon Watkins, Alberto Vazquez, Angus W Thomson, Jun Chen, Weifeng Yu, Xiaoming Hu
BACKGROUND: Despite recent evidence demonstrating a potent protective effect of adoptively transferred regulatory T cells (Tregs) in ischemic stroke, the mechanism for Treg mobilization and activation in the ischemic brain is, remarkably, unknown. This study determines the role of C-C chemokine receptor type 5 (CCR5) in mediating the docking and activation of transferred Tregs in their protection of early blood-brain barrier disruption after stroke. METHODS AND RESULTS: Adoptive transfer of CCR5(-/-) Tregs failed to reduce brain infarct or neurological deficits, indicating an indispensable role of CCR5 in Treg-afforded protection against cerebral ischemia...
August 2, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28764981/promises-and-limitations-of-nanoparticles-in-the-era-of-cell-therapy-example-with-cd19-targeting-chimeric-antigen-receptor-car-modified-t-cells
#14
Hélène Jakobczyk, Flavien Sciortino, Soizic Chevance, Fabienne Gauffre, Marie-Bérengère Troadec
A number of nanoparticles has been developed by chemists for biomedical applications to meet imaging and targeting needs. In parallel, adoptive T therapy with chimeric antigen receptor engineered T cells (CART cells) has recently held great promise in B-cell malignancy treatments thanks to the development of anti-CD19 CAR T cells. Indeed, CD19 is a reliable B cell marker and a validated target protein for therapy. In this perspective article, we propose to discuss the advantages, limits and challenges of nanoparticles and CAR T cells, focusing on CD19 targeting objects: anti-CD19 nanoparticles and anti-CD19 CAR T cells, because those genetically-modified cells are the most widely developed in clinical setting...
July 29, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28763790/platelets-subvert-t-cell-immunity-against-cancer-via-garp-tgf%C3%AE-axis
#15
Saleh Rachidi, Alessandra Metelli, Brian Riesenberg, Bill X Wu, Michelle H Nelson, Caroline Wallace, Chrystal M Paulos, Mark P Rubinstein, Elizabeth Garrett-Mayer, Mirko Hennig, Daniel W Bearden, Yi Yang, Bei Liu, Zihai Li
Cancer-associated thrombocytosis has long been linked to poor clinical outcome, but the underlying mechanism is enigmatic. We hypothesized that platelets promote malignancy and resistance to therapy by dampening host immunity. We show that genetic targeting of platelets enhances adoptive T cell therapy of cancer. An unbiased biochemical and structural biology approach established transforming growth factor β (TGFβ) and lactate as major platelet-derived soluble factors to obliterate CD4(+) and CD8(+) T cell functions...
May 5, 2017: Science Immunology
https://www.readbyqxmd.com/read/28761354/pd-1-blockade-restores-impaired-function-of-ex-vivo-expanded-cd8-t-cells-and-enhances-apoptosis-in-mismatch-repair-deficient-epcam-pd-l1-cancer-cells
#16
Rajeev Kumar, Fang Yu, Yuan-Huan Zhen, Bo Li, Jun Wang, Yuan Yang, Hui-Xin Ge, Ping-Sheng Hu, Jin Xiu
BACKGROUND: Adoptive T cell therapy has been proven to be a promising modality for the treatment of cancer patients in recent years. However, the increased expression of inhibitory receptors could negatively regulate the function and persistence of transferred T cells which mediates T cell anergy, exhaustion, and tumor regression. In this study, we investigated increased cytotoxic activity after the blockade of PD-1 for effective immunotherapy. METHODS: The cytotoxic function of expanded CD8(+) CTLs and interactions with tumor cells investigated after blocking of PD-1...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28757080/a-fusion-receptor-as-a-safety-switch-detection-and-purification-biomarker-for-adoptive-transferred-t-cells
#17
Xiuqi Wu, Bizhi Shi, Jiqin Zhang, Zhimin Shi, Shengmeng Di, Minliang Fan, Huiping Gao, Hai Wang, Jianren Gu, Hua Jiang, Zonghai Li
The incorporation of an endogenous safety switch represents a rational strategy for the control of toxicities following the administration of adoptive T cell therapies. An ideal safety switch should be capable of depleting the transferred T cells with minimal injury to normal tissues. We generated a fusion receptor by engineering a cryptic 806 epitope of human epidermal growth factor receptor (EGFR) into the N terminus of the full-length human folate receptor 1 (FOLR1), designated as FR806. The expression of FR806 allows transduced T cells to be targeted with CH12, a monoclonal antibody recognizing the 806 epitope, but not wild-type EGFR in healthy tissues...
July 3, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28755856/th9-cells-induce-steroid-resistant-bronchial-hyperresponsiveness-in-mice
#18
Mayumi Saeki, Osamu Kaminuma, Tomoe Nishimura, Noriko Kitamura, Akio Mori, Takachika Hiroi
BACKGROUND: Reduced responsiveness to corticosteroid therapy is a major problem for patients with severe asthma. Although Th9 cells, along with Th2 cells, facilitate antigen-induced airway eosinophilia and bronchial hyperresponsiveness (BHR), the sensitivity of Th9 cell-mediated responses to steroid therapy remains unknown. In this study, we investigated the effect of dexamethasone (Dex) on antigen-induced airway inflammation in Th9 cell-transferred mice. METHODS: Ovalbumin (OVA)-specific Th2 and Th9 cells were polarized from the CD4(+) T cells of DO11...
July 26, 2017: Allergology International: Official Journal of the Japanese Society of Allergology
https://www.readbyqxmd.com/read/28754817/multifaceted-role-of-btla-in-the-control-of-cd8-t-cell-fate-after-antigen-encounter
#19
Krit Ritthipichai, Cara Haymaker, Melisa Martinez-Paniagua, Andrew Aschenbrenner, Xiaohui Yi, Minying Zhang, Charuta Kale, Yared Hailemichael, Willem W Overwijk, Luis Vence, Jason Roszik, Navin Varadarajan, Roza Nurieva, Laszlo G Radvanyi, Patrick Hwu, Chantale Bernatchez
Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40-50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte attenuator) expression on transferred CD8(+) TIL was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8(+)BTLA(+)TIL subset and define the contribution of the Grb2 motif of BTLA in T cell co-stimulation...
July 28, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28752715/-advances-in-application-of-adoptive-t-cell-therapy-for-cancer-patients
#20
Zou Jixia, Zhang Chengyan, Wang Pingli
Adoptive T-cell therapy is the administration of tumor cytotoxic T-cells derived from either patient himself or donors, which were induced or genetically engineered and expanded in vitro, and then injected into patients. Several strategies for adoptive T-cell therapy have been developed since last 30 years. From lymphokine-activated killer cells, tumor-infiltrating lymphocytes, cytokine-induced killer cells, to gene-modified T-cells and tumor associated antigen (TAA)-specific cytotoxic T-cells, the adoptive T-cell therapy has been moving forward to more precise tumor targeting and more effective in elimination of cancer cells...
March 25, 2017: Zhejiang da Xue Xue Bao. Yi Xue Ban, Journal of Zhejiang University. Medical Sciences
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