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(ox40 OR cd28 OR cd137 OR 4-1BB OR GITR OR ICOS OR CD27 OR CD40) AND (chimeric antigen receptor)

Christopher W Helsen, Joanne A Hammill, Vivian W C Lau, Kenneth A Mwawasi, Arya Afsahi, Ksenia Bezverbnaya, Lisa Newhook, Danielle L Hayes, Craig Aarts, Bojana Bojovic, Galina F Denisova, Jacek M Kwiecien, Ian Brain, Heather Derocher, Katy Milne, Brad H Nelson, Jonathan L Bramson
Engineering T cells with chimeric antigen receptors (CARs) is an effective method for directing T cells to attack tumors, but may cause adverse side effects such as the potentially lethal cytokine release syndrome. Here the authors show that the T cell antigen coupler (TAC), a chimeric receptor that co-opts the endogenous TCR, induces more efficient anti-tumor responses and reduced toxicity when compared with past-generation CARs. TAC-engineered T cells induce robust and antigen-specific cytokine production and cytotoxicity in vitro, and strong anti-tumor activity in a variety of xenograft models including solid and liquid tumors...
August 3, 2018: Nature Communications
Viktória Golumba-Nagy, Johannes Kuehle, Andreas A Hombach, Hinrich Abken
Adoptive cell therapy with chimeric antigen receptor (CAR)-redirected T cells induced spectacular regressions of leukemia and lymphoma, however, failed so far in the treatment of solid tumors. A cause is thought to be T cell repression through TGF-β, which is massively accumulating in the tumor tissue. Here, we show that T cells with a CD28-ζ CAR, but not with a 4-1BB-ζ CAR, resist TGF-β-mediated repression. Mechanistically, LCK activation and consequently IL-2 release and autocrine IL-2 receptor signaling mediated TGF-β resistance; deleting the LCK-binding motif in the CD28 CAR abolished both IL-2 secretion and TGF-β resistance, while IL-2 add-back restored TGF-β resistance...
July 10, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Sophia Stock, Jean-Marc Hoffmann, Maria-Luisa Schubert, Lei Wang, Sanmei Wang, Wenjie Gong, Brigitte Neuber, Ulrike Gern, Anita Schmitt, Carsten Müller-Tidow, Peter Dreger, Michael Schmitt, Leopold Sellner
Introduction Enhanced in vivo expansion, long-term persistence of chimeric antigen receptor T (CART) cells and efficient tumor eradication through these cells are linked to the proportion of less-differentiated cells in the CART cell product. Retronectin is well established as an adjuvant for improved retroviral transduction while its property to enrich less-differentiated T cells is less known. In order to increase these subsets, we investigated effects of retronectin-mediated T cell activation for CD19-specific CART cell production...
July 19, 2018: Human Gene Therapy
Ai-Hong Zhang, Jeongheon Yoon, Yong Chan Kim, David W Scott
Controlling immune responses in autoimmunity and to biotherapeutics is an unmet need. In hemophilia, for example, up to one third of patients receiving therapeutic factor VIII (FVIII) infusions develop neutralizing Abs termed "inhibitors." To address this problem in a mouse model of hemophilia A, we used an Ag-specific regulatory T cell (Treg) approach in which we created a novel B cell-targeting chimeric receptor composed of an FVIII Ag domain linked with the CD28-CD3ζ transmembrane and signaling domains...
July 18, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Benjamin O Tschumi, Nina Dumauthioz, Bastien Marti, Lianjun Zhang, Pascal Schneider, Jean-Pierre Mach, Pedro Romero, Alena Donda
Adoptive transfer of T cells transduced with Chimeric Antigen Receptors (CAR) are now FDA-approved for the treatment of B-cell malignancies. Yet, the functionality of the endogenous TCR in CART cells has not been fully assessed. Here, we demonstrate that CART cells progressively upregulate Fas, FasL, DR5 and TRAIL, which result in their programmed cell death, independently of antigen-mediated TCR or CAR activation. CART cell apoptosis occurs even when the CAR contains a single (co-)activatory domain such as CD3ζ, CD28 or 4-1BB...
July 13, 2018: Journal for Immunotherapy of Cancer
Yali Han, Wei Xie, De-Gang Song, Daniel J Powell
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive disease that currently lacks effective targeted therapy. NKG2D ligands (NKG2DLs) are expressed on various tumor types and immunosuppressive cells within tumor microenvironments, providing suitable targets for cancer therapy. METHODS: We applied a chimeric antigen receptor (CAR) approach for the targeting of NKG2DLs expressed on human TNBCs. Lentiviral vectors were used to express the extracellular domain of human NKG2D that binds various NKG2DLs, fused to signaling domains derived from T cell receptor CD3 zeta alone or with CD27 or 4-1BB (CD137) costimulatory domain...
July 6, 2018: Journal of Hematology & Oncology
Ayguen Sahin, Carlos Sanchez, Szofia Bullain, Peter Waterman, Ralph Weissleder, Bob S Carter
Glioblastoma multiforme (GBM) is the most aggressive and deadly form of adult brain cancer. Despite of many attempts to identify potential therapies for this disease, including promising cancer immunotherapy approaches, it remains incurable. To address the need of improved persistence, expansion, and optimal antitumor activity of T-cells in the glioma milieu, we have developed an EGFRvIII-specific third generation (G3-EGFRvIII) chimeric antigen receptor (CAR) that expresses both co-stimulatory factors CD28 and OX40 (MR1-CD8TM-CD28-OX40-CD3ζ)...
2018: PloS One
Hua-Ping Wei, Nan Yang, Zhen-Yang Gu, Sha-Sha Zhao, Fei-Yan Wang, Lan Luo, Li-Xun Guan, Chun-Ji Gao
OBJECTIVE: To explore the killing effect of CAR (CD138-CD28-CD3ζ)-NK cells on myeloma cells through construction of CAR(CD138-CD28-CD3)-NK cells. METHODS: The antiCD138scFv-CD28-CD3 zeta plasmid pcDNA3.1 was constructed, which then together with 3 plasmid lentiviral packaging system were transfected into 293T cells, the virus was collected. Furthermore, in order to get the stably transfected cell line, the NK92MI cell line was infected by the virus, then the positive cells were screened by puromycin...
June 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Jiasen Xie, Zishan Zhou, Shunchang Jiao, Xiaokun Li
A chimeric antigen receptor (CAR) is a type of fusion protein that comprises an antigen-recognition domain and signaling domains. In the present study, a programmed death-ligand 1 (PD-L1)-specific CAR, comprised of a single-chain variable fragment (scFv) derived from a monoclonal antibody, co-stimulatory domains of cluster of differentiation (CD) 28 and 4-1BB and a T-cell-activation domain derived from CD3ζ, was designed. The construction was cloned and packaged into the lentiviral vector pLVX. Flow cytometry confirmed that peripheral blood mononuclear cells were efficiently transduced and that the CAR was successfully expressed on T cells...
July 2018: Oncology Letters
Mark B Geyer, Isabelle Rivière, Brigitte Sénéchal, Xiuyan Wang, Yongzeng Wang, Terence J Purdon, Meier Hsu, Sean M Devlin, Elizabeth Halton, Nicole Lamanna, Jurgen Rademaker, Michel Sadelain, Renier J Brentjens, Jae H Park
Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab...
June 14, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Simone Krebs, Afruja Ahad, Lukas Carter, Justin Eyquem, Christian Brand, Meghan Bell, Vladimir Ponomarev, Thomas Reiner, Claude F Meares, Stephen Gottschalk, Michel Sadelain, Steven M Larson, Wolfgang Andreas Weber
There remains an urgent need for the non-invasive tracking of transfused chimeric antigen receptor (CAR) T cells to determine their biodistribution, viability, expansion, and anti-tumor functionality. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) antibody reporter 1 (DAbR1) comprises a single-chain fragment of the anti-lanthanoid-DOTA antibody 2D12.5/G54C fused to the human CD4-transmembrane domain and binds irreversibly to lanthanoid-(S)-2-(4-acrylamidobenzyl)-DOTA (AABD). The aim of this study was to investigate whether DAbR1 can be expressed on lymphocytes and used as a reporter gene as well as a suicide gene for therapy of immune-related adverse effects...
June 14, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
De-Xiu Bu, Reshma Singh, Eugene E Choi, Marco Ruella, Selene Nunez-Cruz, Keith G Mansfield, Paul Bennett, Nathanial Barton, Qilong Wu, Jiquan Zhang, Yongqiang Wang, Lai Wei, Shawn Cogan, Tucker Ezell, Shree Joshi, Kellie J Latimer, Brian Granda, William R Tschantz, Regina M Young, Heather A Huet, Celeste J Richardson, Michael C Milone
Multiple myeloma has a continued need for more effective and durable therapies. B cell maturation antigen (BCMA), a plasma cell surface antigen and member of the tumor necrosis factor (TNF) receptor superfamily, is an attractive target for immunotherapy of multiple myeloma due to its high prevalence on malignant plasma cells. The current work details the pre-clinical evaluation of BCMA expression and development of a chimeric antigen receptor (CAR) targeting this antigen using a fully human single chain variable fragment (scFv)...
May 25, 2018: Oncotarget
Trudy Straetemans, Guido J J Kierkels, Ruud Doorn, Koen Jansen, Sabine Heijhuurs, Joao M Dos Santos, Anna D D van Muyden, Henri Vie, Béatrice Clemenceau, Reinier Raymakers, Moniek de Witte, Zsolt Sebestyén, Jürgen Kuball
γ9δ2T cells play a critical role in daily cancer immune surveillance by sensing cancer-mediated metabolic changes. However, a major limitation of the therapeutic application of γ9δ2T cells is their diversity and regulation through innate co-receptors. In order to overcome natural obstacles of γ9δ2T cells, we have developed the concept of T cells engineered to express a defined γδT cell receptor (TEGs). This next generation of chimeric antigen receptor engineered T (CAR-T) cells not only allows for targeting of hematological but also of solid tumors and, therefore, overcomes major limitations of many CAR-T and γδT cell strategies...
2018: Frontiers in Immunology
Minsung Kim, Suhkneung Pyo, Chung Hyo Kang, Chong Ock Lee, Heung Kyoung Lee, Sang Un Choi, Chi Hoon Park
Gastric cancer is a malignancy that has a high mortality rate. Although progress has been made in the treatment of gastric cancer, many patients experience cancer recurrence and metastasis. Folate receptor 1 (FOLR1) is overexpressed on the cell surface in over one-third of gastric cancer patients, but rarely is expressed in normal tissue. This makes FOLR1 a potential target for chimeric antigen receptor (CAR) T cell immunotherapy, although the function of FOLR1 has not been elucidated. CAR are engineered fusion receptor composed of an antigen recognition region and signaling domains...
2018: PloS One
Concetta Quintarelli, Domenico Orlando, Iolanda Boffa, Marika Guercio, Vinicia Assunta Polito, Andrea Petretto, Chiara Lavarello, Matilde Sinibaldi, Gerrit Weber, Francesca Del Bufalo, Ezio Giorda, Marco Scarsella, Stefania Petrini, Daria Pagliara, Franco Locatelli, Biagio De Angelis, Ignazio Caruana
Chimeric antigen receptor (CAR) T-cell therapy has been shown to be dramatically effective in the treatment of B-cell malignancies. However, there are still substantial obstacles to overcome, before similar responses can be achieved in patients with solid tumors. We evaluated both in vitro and in a preclinical murine model the efficacy of different 2nd and 3rd generation CAR constructs targeting GD2, a disial-ganglioside expressed on the surface of neuroblastoma (NB) tumor cells. In order to address potential safety concerns regarding clinical application, an inducible safety switch, namely inducible Caspase-9 (iC9), was also included in the vector constructs...
2018: Oncoimmunology
Yunliang Yao, Wei Huang, Xiaoyu Li, Xiawei Li, Jin Qian, Hui Han, Hui Sun, Xiangli An, Linrong Lu, Hongxing Zhao
Thymocyte-expressed, positive selection-associated 1 ( Tespa1 ) plays an important role in both T cell receptor (TCR)-driven thymocyte development and in the FcεRI-mediated activation of mast cells. Herein, we show that lack of Tespa1 does not impair B cell development but dampens the in vitro activation and proliferation of B cells induced by T cell-dependent (TD) antigens, significantly reduces serum antibody concentrations in vivo , and impairs germinal center formation in both aged and TD antigen-immunized mice...
2018: Frontiers in Immunology
David C Bishop, Ning Xu, Benjamin Tse, Tracey A O'Brien, David J Gottlieb, Alla Dolnikov, Kenneth P Micklethwaite
Clinical trials of CD19-specific chimeric antigen receptor (CAR19) T cells have demonstrated remarkable efficacy against relapsed and refractory B cell malignancies. The piggyBac transposon system offers a less complex and more economical means for generating CAR19 T cells compared to viral vectors. We have previously optimized a protocol for the generation of CAR19 T cells using the piggyBac system, but we found that CAR19 T cells had poor in vivo efficacy and persistence, probably due to deleterious FcγR interactions with the CAR's IgG1 Fc-containing spacer domain...
June 1, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Andrew J Rech, Hannah Dada, Jonathan J Kotzin, Jorge Henao-Mejia, Andy J Minn, Christina Twyman-Saint Victor, Robert H Vonderheide
Immunotherapy in pancreatic ductal adenocarcinoma (PDA) remains a difficult clinical problem despite success in other disease types with immune checkpoint blockade (ICB) and chimeric antigen receptor T cell therapy. Mechanisms driving immunosuppression and poor T cell infiltration in PDA are incompletely understood. Here we use genetically engineered mouse models of PDA that recapitulate hallmarks of human disease to demonstrate that CD40 pathway activation is required for clinical response to radiotherapy (RT) and ICB with αCTLA-4 and αPD-1...
May 29, 2018: Cancer Research
Vita M Golubovskaya, Robert Berahovich, Qumiao Xu, Hua Zhou, Shirley Xu, Jasper Guan, Hizkia Harto, Le Li, Lijun Wu
T cells expressing Chimeric antigen receptors or CAR-T cells are used as a novel treatment against hematological and solid cancers. In this report, we designed CAR with glucocorticoid-induced TNFR-related protein (GITR) co-stimulatory domain to study its ability to co-activate CAR-T cells. EGFR-GITR-CD3 CAR-T cells were cytotoxic against EGFR-positive: pancreatic and ovarian cancer cells but not against EGFR-negative cancer cells. The cytotoxic activity of EGFR-GITR-CD3 CAR-T cells was comparable or better than EGFR-28-CD3 or EGFR-41BB-CD3 CAR-T cells...
June 1, 2018: Frontiers in Bioscience (Landmark Edition)
Pratiksha Gulati, Julia Rühl, Abhilash Kannan, Magdalena Pircher, Petra Schuberth, Katarzyna J Nytko, Martin Pruschy, Simon Sulser, Mark Haefner, Shawn Jensen, Alex Soltermann, Wolfgang Jungraithmayr, Maya Eisenring, Thomas Winder, Panagiotis Samaras, Annett Tabor, Rene Stenger, Roger Stupp, Walter Weder, Christoph Renner, Christian Münz, Ulf Petrausch
Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. Experimental Design: Fibroblast activation protein (FAP)-specific CARs with different costimulatory domains, including CD28, Δ-CD28 (lacking lck binding moiety), or 4-1BB were established...
May 10, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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