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Adoptive T cell therapy

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https://www.readbyqxmd.com/read/28237836/inhibitory-receptors-induced-by-vsv-viroimmunotherapy-are-not-necessarily-targets-for-improving-treatment-efficacy
#1
Kevin G Shim, Shane Zaidi, Jill Thompson, Tim Kottke, Laura Evgin, Karishma R Rajani, Matthew Schuelke, Christopher B Driscoll, Amanda Huff, Jose S Pulido, Richard G Vile
Systemic viroimmunotherapy activates endogenous innate and adaptive immune responses against both viral and tumor antigens. We have shown that therapy with vesicular stomatitis virus (VSV) engineered to express a tumor-associated antigen activates antigen-specific adoptively transferred T cells (adoptive cell therapy, ACT) in vivo to generate effective therapy. The overall goal of this study was to phenotypically characterize the immune response to VSV+ACT therapy and use the information gained to rationally improve combination therapy...
February 22, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28237835/integration-of-a-cd19-car-into-the-tcr-alpha-chain-locus-streamlines-production-of-allogeneic-gene-edited-car-t-cells
#2
Daniel T MacLeod, Jeyaraj Antony, Aaron J Martin, Rachel J Moser, Armin Hekele, Keith J Wetzel, Audrey E Brown, Melissa A Triggiano, Jo Ann Hux, Christina D Pham, Victor V Bartsevich, Caitlin A Turner, Janel Lape, Samantha Kirkland, Clayton W Beard, Jeff Smith, Matthew L Hirsch, Michael G Nicholson, Derek Jantz, Bruce McCreedy
Adoptive cellular therapy using chimeric antigen receptor (CAR) T cell therapies have produced significant objective responses in patients with CD19(+) hematological malignancies, including durable complete responses. Although the majority of clinical trials to date have used autologous patient cells as the starting material to generate CAR T cells, this strategy poses significant manufacturing challenges and, for some patients, may not be feasible because of their advanced disease state or difficulty with manufacturing suitable numbers of CAR T cells...
February 22, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28231431/enhancing-adoptive-cell-therapy-of-cancer-through-targeted-delivery-of-small-molecule-immunomodulators-to-internalizing-or-non-internalizing-receptors
#3
Yiran Zheng, Li Tang, Llian Mabardi, Sudha Kumari, Darrell J Irvine
Adoptive cell therapy (ACT) has achieved striking efficacy in B-cell leukemias, but less success treating other cancers, in part due to the rapid loss of ACT T-cell effector function in vivo due to immunosuppression in solid tumors. Transforming growth factor-β (TGF-β) signaling is an important mechanism of immune suppression in the tumor microenvironment, but systemic inhibition of TGF-β is toxic. Here we evaluated the potential of targeting a small molecule inhibitor of TGF-β to ACT T-cells using PEGylated immunoliposomes...
February 23, 2017: ACS Nano
https://www.readbyqxmd.com/read/28226463/cardiac-katp-channel-modulation-by-16hz-magnetic-fields-a-theoretical-study
#4
Yuval Aharonovich, Mickey Scheinowitz, Sharon Zlochiver, Yuval Aharonovich, Mickey Scheinowitz, Sharon Zlochiver, Yuval Aharonovich, Sharon Zlochiver, Mickey Scheinowitz
Heart exposure to 16Hz magnetic fields (MFs) was shown to be cardio-protective for diseased hearts; still, the mechanism of this effect is unknown. We hypothesize that a possible one mechanism is an increased trans-membrane KATP channel open probability due to modulation of the degree of dissociation between K(+) ions, having a resonance frequency of 16Hz, and the channel selectivity filter. The Fan-Makielski Markovian KATP channel model was adopted, and the MF bio-effect was manifested by modulating the open probability of the channel using the predictive MF bio-effect parameter based on Binhi's quantum mechanics model...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28223693/single-cd28-stimulation-induces-stable-and-polyclonal-expansion-of-human-regulatory-t-cells
#5
Xuehui He, Ruben L Smeets, Esther van Rijssen, Annemieke M H Boots, Irma Joosten, Hans J P M Koenen
CD4+FOXP3+ Treg are essential for immune tolerance. Phase-1 clinical trials of Treg-therapy to treat graft-versus-host-disease reported safety and potential therapeutic efficacy. Treg-based trials have started in organ-transplant patients. However, efficient ex vivo expansion of a stable Treg population remains a challenge and exploring novel ways for Treg expansion is a pre-requisite for successful immunotherapy. Based on the recent finding that CD28-signaling is crucial for survival and proliferation of mouse Treg, we studied single-CD28 stimulation of human Treg, without T cell receptor stimulation...
February 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28223167/intracavitary-t4-immunotherapy-of-malignant-mesothelioma-using-pan-erbb-re-targeted-car-t-cells
#6
Astero Klampatsa, Daniela Y Achkova, David M Davies, Ana C Parente-Pereira, Natalie Woodman, James Rosekilly, Georgina Osborne, Thivyan Thayaparan, Andrea Bille, Michael Sheaf, James F Spicer, Juliet King, John Maher
Malignant mesothelioma remains an incurable cancer. We demonstrated that mesotheliomas expressed EGFR (79.2%), ErbB4 (49.0%) and HER2 (6.3%), but lacked ErbB3. At least one ErbB family member was expressed in 88% of tumors. To exploit ErbB dysregulation in this disease, patient T-cells were engineered by retroviral transduction to express a panErbB-targeted chimeric antigen receptor (CAR), co-expressed with a chimeric cytokine receptor that allows interleukin (IL)-4 mediated CAR T-cell proliferation. This combination is referred to as T4 immunotherapy...
February 20, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28219891/peripherally-generated-foxp3-regulatory-t-cells-mediate-the-immunomodulatory-effects-of-ivig-in-allergic-airways-disease
#7
Amir H Massoud, Gabriel N Kaufman, Di Xue, Marianne Béland, Marieme Dembele, Ciriaco A Piccirillo, Walid Mourad, Bruce D Mazer
IVIg is widely used as an immunomodulatory therapy. We have recently demonstrated that IVIg protects against airway hyperresponsiveness (AHR) and inflammation in mouse models of allergic airways disease (AAD), associated with induction of Foxp3(+) regulatory T cells (Treg). Using mice carrying a DTR/EGFP transgene under the control of the Foxp3 promoter (DEREG mice), we demonstrate in this study that IVIg generates a de novo population of peripheral Treg (pTreg) in the absence of endogenous Treg. IVIg-generated pTreg were sufficient for inhibition of OVA-induced AHR in an Ag-driven murine model of AAD...
February 20, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28216433/lifelong-memory-responses-perpetuate-humoral-th2-immunity-and-anaphylaxis-in-food-allergy
#8
Rodrigo Jiménez-Saiz, Derek K Chu, Talveer S Mandur, Tina D Walker, Melissa E Gordon, Roopali Chaudhary, Joshua Koenig, Sarah Saliba, Heather J Galipeau, Adam Utley, Irah L King, Kelvin Lee, Rachel Ettinger, Susan Waserman, Roland Kolbeck, Manel Jordana
BACKGROUND: A number of food allergies (e.g. fish, shellfish, nuts) are lifelong, without any disease-transforming therapies and unclear in their underlying immunology. Clinical manifestations of food allergy are largely mediated by IgE. Although persistent IgE titres have conventionally been attributed to long-lived IgE(+) plasma cells (PCs), this has not been directly and comprehensively tested. OBJECTIVE: To evaluate mechanisms underlying persistent IgE and allergic responses to food allergens...
February 16, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28202953/fully-human-cd19-specific-chimeric-antigen-receptors-for-t-cell-therapy
#9
D Sommermeyer, T Hill, S M Shamah, A I Salter, Y Chen, K M Mohler, S R Riddell
Impressive results have been achieved by adoptively transferring T-cells expressing CD19-specific CARs with binding domains from murine mAbs to treat B-cell malignancies. T-cell mediated immune responses specific for peptides from the murine scFv antigen-binding domain of the CAR can develop in patients and result in premature elimination of CAR-T-cells increasing the risk of tumor relapse. As fully human scFv might reduce immunogenicity, we generated CD19-specific human scFvs with similar binding characteristics as the murine FMC63-derived scFv using human Ab/DNA-libraries...
February 16, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28197365/crispr-cas9-mediated-disruption-of-pd-1-on-human-t-cells-for-adoptive-cellular-therapies-of-ebv-positive-gastric-cancer
#10
Shu Su, Zhengyun Zou, Fangjun Chen, Naiqing Ding, Juan Du, Jie Shao, Lin Li, Yao Fu, Bian Hu, Yang Yang, Huizi Sha, Fanyan Meng, Jia Wei, Xingxu Huang, Baorui Liu
The successful use of immune cell checkpoint inhibitors PD-1 and PD-L1, over the past 5 y has raised the concern of using immunotherapy to treat various cancers. Epstein-Barr virus-associated gastric cancer (EBVaGC) exhibits high infiltration of lymphocytes and high amplification of immune-related genes including PD-L1 as distinguished from Epstein-Barr virus-non-associated gastric cancer (EBVnGC). Here, we presume that this PD-1/PD-L1 pathway may hinder the efficacy of adoptive T cell therapy toward EBVaGC...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28193627/adoptive-transfer-of-invariant-nkt-cells-as-immunotherapy-for-advanced-melanoma-a-phase-1-clinical-trial
#11
Mark A Exley, Philip Friedlander, Nadia Alatrakchi, Lianne Vriend, Simon C Yue, Tetsuro Sasada, Wanyong Zang, Yo Mizukami, Justice Clark, David Nemer, Ken LeClair, Christine Canning, Heather Daley, Glenn Dranoff, Anita Giobbie-Hurder, F Stephen Hodi, Jerome Ritz, Steven P Balk
PURPOSE: Invariant NKT cells (iNKT) are innate-like CD1d-restricted T cells with immunoregulatory activity in diseases including cancer. iNKT from advanced cancer patients can have reversible defects including IFNγ production, and iNKT IFNγ production may stratify for survival. Previous clinical trials using iNKT cell activating ligand α-galactosylceramide have shown responses. Therefore, a phase 1 clinical trial was performed of autologous in vitro expanded iNKT cells in stage IIIB-IV melanoma...
February 13, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28184969/augmented-anti-tumor-activity-of-nk-92-cells-expressing-chimeric-receptors-of-tgf-%C3%AE-r-ii-and-nkg2d
#12
Zhongjuan Wang, Linghua Guo, Yuan Song, Yinsheng Zhang, Dandan Lin, Bo Hu, Yu Mei, Dedy Sandikin, Haiyan Liu
The capacity of natural killer (NK) cells to kill tumor cells without specific antigen recognition provides an advantage over T cells and makes them potential effectors for tumor immunotherapy. However, the efficacy of NK cell adoptive therapy can be limited by the immunosuppressive tumor microenvironment. Transforming growth factor-β (TGF-β) is a potent immunosuppressive cytokine that can suppress NK cell function. To convert the suppressive signal induced by TGF-β to an activating signal, we genetically modified NK-92 cells to express a chimeric receptor with TGF-β type II receptor extracellular and transmembrane domains and the intracellular domain of NK cell-activating receptor NKG2D (TN chimeric receptor)...
February 9, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28183349/hif-1%C3%AE-inhibitor-echinomycin-reduces-acute-graft-versus-host-disease-and-preserves-graft-versus-leukemia-effect
#13
Yushi Yao, Lei Wang, Jihao Zhou, Xinyou Zhang
BACKGROUND: Acute graft-versus-host disease (aGVHD) remains a major obstacle against favorable clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). T helper cells including Th17 play key roles in aGVHD pathogenesis. Donor regulatory T cell (Tregs) adoptive therapy reduces aGVHD without weakening graft-versus-leukemia effect (GVL) in both mouse and human, although the purification and ex vivo expansion of Tregs in clinical scenarios remain costly and technically demanding...
February 10, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28179501/drug-discovery-for-diamond-blackfan-anemia-using-reprogrammed-hematopoietic-progenitors
#14
Sergei Doulatov, Linda T Vo, Elizabeth R Macari, Lara Wahlster, Melissa A Kinney, Alison M Taylor, Jessica Barragan, Manav Gupta, Katherine McGrath, Hsiang-Ying Lee, Jessica M Humphries, Alex DeVine, Anupama Narla, Blanche P Alter, Alan H Beggs, Suneet Agarwal, Benjamin L Ebert, Hanna T Gazda, Harvey F Lodish, Colin A Sieff, Thorsten M Schlaeger, Leonard I Zon, George Q Daley
Diamond-Blackfan anemia (DBA) is a congenital disorder characterized by the failure of erythroid progenitor differentiation, severely curtailing red blood cell production. Because many DBA patients fail to respond to corticosteroid therapy, there is considerable need for therapeutics for this disorder. Identifying therapeutics for DBA requires circumventing the paucity of primary patient blood stem and progenitor cells. To this end, we adopted a reprogramming strategy to generate expandable hematopoietic progenitor cells from induced pluripotent stem cells (iPSCs) from DBA patients...
February 8, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28174424/targeting-a2-adenosine-receptors-in-cancer
#15
REVIEW
David Allard, Martin Turcotte, John Stagg
Tumor cells use various ways to evade antitumor immune responses. Adenosine, a potent immunosuppressive metabolite, is often found elevated in the extracellular tumor microenvironment. Therefore, targeting adenosine-generating enzymes (CD39 and CD73) or adenosine receptors has emerged as a novel means to stimulate antitumor immunity. In particular, the A2 (A2a and A2b) adenosine receptors exhibit similar immunosuppressive and pro-angiogenic functions, yet have distinct biological roles in cancer. In this review, we describe the common and distinct biological consequences of A2a and A2b adenosine receptor signaling in cancer...
February 8, 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28162024/immunotherapeutic-strategies-for-the-treatment-of-renal-cell-carcinoma-where-will-we-go
#16
Inês Anselmo da Costa, Steffen Rausch, Stephan Kruck, Tilman Todenhöfer, Arnulf Stenzl, Jens Bedke
Historically, renal cell carcinoma (RCC) is considered a chemotherapy-resistant tumor. The cornerstone of systemic therapy included mammalian target of rapamycin (mTOR) inhibitors, endothelial growth factor receptor (VEGFR) and tyrosine kinase inhibitors (TKIs). Currently, a new era is enteres with promising immunotherapeutic treatments, which are becoming commercially available. Areas covered: We provide a comprehensive review using PubMed and ClinicalTrials.gov about the following immunotherapies in RCC: i) vaccine therapy, ii) adoptive T Cell Transfer and CAR T cells, iii) nonspecific immunotherapy-IL-2 (new formulations), iv) Checkpoint inhibitors, v) other checkpoint-molecules...
February 4, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/28152953/cost-effectiveness-of-brentuximab-vedotin-in-relapsed-or-refractory-systemic-anaplastic-large-cell-lymphoma
#17
Denise Zou, Esprit Ma, Peter Sajosi, Andreas Engstrom, Ross Selby, Eugene Benson, Jeremy Teasell, Akshara Richhariya, Andrew Briggs, Vijayveer Bonthapally
: 18 Background: Systemic anaplastic large cell lymphoma (sALCL) is a rare T-cell lymphoma. For patients who fail front-line therapy, outcomes are poor and there is no current defined standard of care. Brentuximab vedotin has demonstrated high objective response rates and is approved for patients with relapsed or refractory (R/R) sALCL. However, the cost-effectiveness of brentuximab vedotin compared with conventional chemotherapy has not been explored. METHODS: A lifetime Excel-based partitioned survival model was used to compare survival outcomes from the pivotal phase-2 single-arm brentuximab vedotin trial of 58 R/R sALCL patients with good Eastern Corporative Oncology Group (ECOG) performance status after one or more prior therapies (SG035-0004); with 40 sALCL patients from a Canadian cancer registry receiving first-line conventional salvage chemotherapy (65% with ECOG 0 or 1) between 1980 and 2012 and followed for up to 20 years...
March 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28140447/myeloid-derived-suppressor-cells-mediate-tolerance-induction-in-autoimmune-disease
#18
Anja Wegner, Johan Verhagen, David C Wraith
In multiple sclerosis (MS) T cells aberrantly recognise self-peptides of the myelin sheath and attack the central nervous system (CNS). Antigen-specific peptide immunotherapy, which aims to restore tolerance while avoiding the use of non-specific immunosuppressive drugs, is a promising approach to combat autoimmune disease, but the cellular mechanisms behind successful therapy remain poorly understood. Myeloid-derived suppressor cells (MDSCs) have been studied intensively in the field of cancer and to a lesser extent in autoimmunity...
January 31, 2017: Immunology
https://www.readbyqxmd.com/read/28138559/transient-stimulation-expands-superior-antitumor-t-cells-for-adoptive-therapy
#19
Yuki Kagoya, Munehide Nakatsugawa, Toshiki Ochi, Yuchen Cen, Tingxi Guo, Mark Anczurowski, Kayoko Saso, Marcus O Butler, Naoto Hirano
Adoptive cell therapy is a potentially curative therapeutic approach for patients with cancer. In this treatment modality, antitumor T cells are exponentially expanded in vitro prior to infusion. Importantly, the results of recent clinical trials suggest that the quality of expanded T cells critically affects their therapeutic efficacy. Although anti-CD3 mAb-based stimulation is widely used to expand T cells in vitro, a protocol to generate T cell grafts for optimal adoptive therapy has yet to be established...
January 26, 2017: JCI Insight
https://www.readbyqxmd.com/read/28138156/antibody-dependent-cell-cytotoxicity-immunotherapy-strategies-enhancing-effector-nk-cells
#20
REVIEW
Maria Carmen Ochoa, Luna Minute, Inmaculada Rodriguez, Saray Garasa, Elisabeth Perez-Ruiz, Susana Inogés, Ignacio Melero, Pedro Berraondo
Antibody-dependent cellular cytotoxicity (ADCC) is a set of mechanisms that target cells coated with IgG antibodies of the proper subclasses (IgG1 in the human) to be the prey of cell-to-cell cytolysis executed by immune cells expressing FcRIIIA (CD16A). These effectors include not only natural killer (NK) cells but also other CD16(+) subsets such as monocyte/macrophages, NKT cells or γδ T cells. In cancer therapy, ADCC is exploited by antibodies that selectively recognize proteins on the surface of malignant cells...
February 21, 2017: Immunology and Cell Biology
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