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https://www.readbyqxmd.com/read/29133316/study-protocol-for-think-a-multinational-open-label-phase-i-study-to-assess-the-safety-and-clinical-activity-of-multiple-administrations-of-nkr-2-in-patients-with-different-metastatic-tumour-types
#1
Caroline Lonez, Bikash Verma, Alain Hendlisz, Philippe Aftimos, Ahmad Awada, Eric Van Den Neste, Gaetan Catala, Jean-Pascal H Machiels, Fanny Piette, Jason B Brayer, David A Sallman, Tessa Kerre, Kunle Odunsi, Marco L Davila, David E Gilham, Frédéric F Lehmann
INTRODUCTION: NKR-2 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) comprising a fusion of the natural killer group 2D (NKG2D) receptor with the CD3ζ signalling domain, which associates with the adaptor molecule DNAX-activating protein of 10 kDa (DAP10) to provide co-stimulatory signal upon ligand binding. NKG2D binds eight different ligands expressed on the cell surface of many tumour cells and which are normally absent on non-neoplastic cells...
November 12, 2017: BMJ Open
https://www.readbyqxmd.com/read/29132473/-progress-in-clinical-studies-of-chimeric-antigen-receptor-engineered-t-cells-for-treatment-of-childhood-cancer
#2
Ya-Ru Ni, Xiao-Jun Xu, Yong-Min Tang
Nowadays, the 5-year survival rate of childhood cancer patients can be more than 80%, but some patients with relapse and refractory cancers have shown no good response to traditional strategies. Chimeric antigen receptor engineered T (CAR-T) cell therapy is promising for these patients. CAR-T cells recognize the tumor-associated antigens in a non-major histocompatibility complex-restricted manner, so their anti-tumor ability is enhanced. There are four generations of CAR-T cells now. The complete remission rate of pediatric patients with relapse and refractory acute lymphoblastic leukemia can be as high as 90% when treated with CD19-targeting CAR-T cells...
November 2017: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
https://www.readbyqxmd.com/read/29132013/chimeric-antigen-receptor-modified-t-cells-redirected-to-epha2-for-the-immunotherapy-of-non-small-cell-lung-cancer
#3
Ning Li, Shaohui Liu, Mingjiao Sun, Wei Chen, Xiaogang Xu, Zhu Zeng, Yemin Tang, Yongquan Dong, Alex H Chang, Qiong Zhao
Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) is overexpressed in more than 90% of non-small cell lung cancer (NSCLC) but not significantly in normal lung tissue. It is therefore an important tumor antigen target for chimeric antigen receptors (CAR)-T-based therapy in NSCLC. Here, we developed a specific CAR targeted to EphA2, and the anti-tumor effects of this CAR were investigated. A second generation CAR with co-stimulatory receptor 4-1BB targeted to EphA2 was developed. The functionality of EphA2-specific T cells in vitro was tested with flow cytometry and real-time cell electronic sensing system assays...
November 10, 2017: Translational Oncology
https://www.readbyqxmd.com/read/29127433/targeting-and-suppression-of-her3-positive-breast-cancer-by-t-lymphocytes-expressing-a-heregulin-chimeric-antigen-receptor
#4
Bai-Le Zuo, Bo Yan, Guo-Xu Zheng, Wen-Jin Xi, Xiao Zhang, An-Gang Yang, Lin-Tao Jia
Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors...
November 10, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29126914/targeting-immuno-metabolism-to-improve-anti-cancer-therapies
#5
Kevin Beezhold, Craig A Byersdorfer
The immunology community has made significant strides in recent years in using the immune system to target and eliminate cancer. Therapies such as hematopoietic stem cell transplantation (HSCT) are the standard of care treatment for several malignancies, while therapies incorporating chimeric antigen receptor (CAR) T cells or checkpoint molecule blockade have been revolutionary. However, these approaches are not optimal for all cancers and in some cases, have failed outright. The greatest obstacle to making these therapies more effective may be rooted in one of the most basic concepts of cell biology, metabolism...
November 7, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29123951/characterization-of-a-switchable-chimeric-antigen-receptor-platform-in-a-pre-clinical-solid-tumor-model
#6
Elham Pishali Bejestani, Marc Cartellieri, Ralf Bergmann, Armin Ehninger, Simon Loff, Michael Kramer, Johannes Spehr, Antje Dietrich, Anja Feldmann, Susann Albert, Martin Wermke, Michael Baumann, Mechthild Krause, Martin Bornhäuser, Gerhard Ehninger, Michael Bachmann, Malte von Bonin
The universal modular chimeric antigen receptor (UniCAR) platform redirects CAR-T cells using a separated, soluble targeting module with a short half-life. This segregation allows precise controllability and flexibility. Herein we show that the UniCAR platform can be used to efficiently target solid cancers in vitro and in vivo using a pre-clinical prostate cancer model which overexpresses prostate stem cell antigen (PSCA). Short-term administration of the targeting module to tumor bearing immunocompromised mice engrafted with human UniCAR-T cells significantly delayed tumor growth and prolonged survival of recipient mice both in a low and high tumor burden model...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29119551/chimeric-antigen-receptor-transduced-t-cells-tuning-up-for-the-next-generation
#7
REVIEW
Maria-Luisa Schubert, Jean-Marc Hoffmann, Peter Dreger, Carsten Müller-Tidow, Michael Schmitt
Chimeric antigen receptor (CAR) T cell therapy has recently achieved impressive clinical outcome in patients with CD19-positive hematologic malignancies. Extrapolation of CAR T cell treatment to solid tumors, however, has not yet yielded similar results. This might be due to intrinsic causes, e.g. insufficient CAR T cell activation or CAR toxicity as well as extrinsic factors displaying an unfavorable tumor environment for CAR T cells by raising physical and chemical barriers. In this review, we discuss the advantages as well as major obstacles of CAR T cell therapy, particularly in the context of solid tumors, and focus on efforts and novel strategies in CAR T cell development...
November 9, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29113941/human-relevance-of-rodent-liver-tumors-key-insights-from-a-toxicology-forum-workshop-on-nongenotoxic-modes-of-action
#8
Susan P Felter, Jennifer E Foreman, Alan Boobis, J Christopher Corton, Adriana M Doi, Lynn Flowers, Jay Goodman, Lynne T Haber, Abigail Jacobs, James E Klaunig, Angela M Lynch, Jonathan Moggs, Arun Pandiri
The Toxicology Forum sponsored a workshop in October 2016, on the human relevance of rodent liver tumors occurring via nongenotoxic modes of action (MOAs). The workshop focused on two nuclear receptor-mediated MOAs (Constitutive Androstane Receptor (CAR) and Peroxisome Proliferator Activated Receptor-alpha (PPARα), and on cytotoxicity. The goal of the meeting was to review the state of the science to (1) identify areas of consensus and differences, data gaps and research needs; (2) identify reasons for inconsistencies in current regulatory positions; and (3) consider what data are needed to demonstrate a specific MOA, and when additional research is needed to rule out alternative possibilities...
November 4, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29110403/live-cell-labeling-with-novel-terpyridine-derivative-proligands-to-measure-cytotoxicity-mediated-by-immune-cells
#9
Yoshimasa Tanaka, Yuki Sakai, Satoshi Mizuta, Asuka Kumagai, Mohamed S O Tagod, Hiroaki Senju, Tatsufumi Nakamura, Craig T Morita
Immunotherapy using immune checkpoint inhibitors and CAR-T cells has revolutionized treatment for patients with malignant tumors. However, measuring tumor cell cytotoxicity mediated by immune effector cells in clinical laboratories has been difficult due to the requirement for radioactive substances. In this study, a series of novel terpyridine derivative proligands were synthesized and a non-radioactive cellular cytotoxicity assay using the newly synthesized compounds was developed for use in preclinical and clinical studies for cancer immunotherapy...
November 7, 2017: ChemMedChem
https://www.readbyqxmd.com/read/29109077/safety-and-efficacy-of-intratumoral-injections-of-chimeric-antigen-receptor-car-t-cells-in-metastatic-breast-cancer
#10
Julia Tchou, Yangbing Zhao, Bruce L Levine, Paul J Zhang, Megan M Davis, Jan Joseph Melenhorst, Irina Kulikovskaya, Andrea L Brennan, Xiajun Liu, Simon F Lacey, Avery Posey, Austin D Williams, Alycia So, Jose R Conejo-Garcia, Gabriela Plesa, Regina M Young, Shannon McGettigan, Jean Campbell, Robert H Pierce, Jennifer M Matro, Angela M DeMichele, Amy S Clark, Laurence J N Cooper, Lynn M Schuchter, Robert H Vonderheide, Carl H June
Chimeric antigen receptors (CARs) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in ~50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602)...
November 6, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29107016/chimeric-antigen-receptor-car-t-cell-therapy-for-thoracic-malignancies
#11
REVIEW
Stefan Kiesgen, Leonardo Chicaybam, Navin K Chintala, Prasad S Adusumilli
Chimeric antigen receptor (CAR) T cells are patient T cells that are transduced with genetically engineered synthetic receptors to target a cancer cell surface antigen. The remarkable clinical response rates achieved by adoptive transfer of T cells that target CD19 in patients with leukemia and lymphoma have led to a growing number of clinical trials exploring CAR T-cell therapy for solid tumors. Herein, we review the evolution of adoptive T-cell therapy, highlight advances in CAR T-cell therapy for thoracic malignancies, and summarize the targets being investigated in clinical trials for patients with lung cancer, malignant pleural mesothelioma, and esophageal cancer...
October 26, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29103912/optimization-of-il13r%C3%AE-2-targeted-chimeric-antigen-receptor-t-cells-for-improved-anti-tumor-efficacy-against-glioblastoma
#12
Christine E Brown, Brenda Aguilar, Renate Starr, Xin Yang, Wen-Chung Chang, Lihong Weng, Brenda Chang, Aniee Sarkissian, Alfonso Brito, James F Sanchez, Julie R Ostberg, Massimo D'Apuzzo, Behnam Badie, Michael E Barish, Stephen J Forman
T cell immunotherapy is emerging as a powerful strategy to treat cancer and may improve outcomes for patients with glioblastoma (GBM). We have developed a chimeric antigen receptor (CAR) T cell immunotherapy targeting IL-13 receptor α2 (IL13Rα2) for the treatment of GBM. Here, we describe the optimization of IL13Rα2-targeted CAR T cells, including the design of a 4-1BB (CD137) co-stimulatory CAR (IL13BBζ) and a manufacturing platform using enriched central memory T cells. Utilizing orthotopic human GBM models with patient-derived tumor sphere lines in NSG mice, we found that IL13BBζ-CAR T cells improved anti-tumor activity and T cell persistence as compared to first-generation IL13ζ-CAR CD8(+) T cells that had shown evidence for bioactivity in patients...
October 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29079655/reversible-transgene-expression-reduces-fratricide-and-permits-4-1bb-costimulation-of-car-t-cells-directed-to-t-cell-malignancies
#13
Maksim Mamonkin, Malini Mukherjee, Madhuwanti Srinivasan, Sandhya Sharma, Diogo Gomes-Silva, Feiyan Mo, Giedre Krenciute, Jordan S Orange, Malcolm K Brenner
T cells expressing second-generation chimeric antigen receptors (CARs) specific for CD5, a T-cell surface marker present on normal and malignant T cells, can selectively kill tumor cells. We aimed to improve this killing by substituting the CD28 costimulatory endodomain (28.z) with 4-1BB (BB.z), as 28.z CD5 CAR T cells rapidly differentiated into short-lived effector cells. In contrast, 4-1BB costimulation is known to promote development of the central memory subpopulation. Here, we found BB.z CD5 CAR T cells had impaired growth compared to 28...
October 27, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29077054/development-of-a-chimeric-antigen-receptor-targeting-c-type-lectin-like-molecule-1-for-human-acute-myeloid-leukemia
#14
Eduardo Laborda, Magdalena Mazagova, Sida Shao, Xinxin Wang, Herlinda Quirino, Ashley K Woods, Eric N Hampton, David T Rodgers, Chan Hyuk Kim, Peter G Schultz, Travis S Young
The treatment of patients with acute myeloid leukemia (AML) with targeted immunotherapy is challenged by the heterogeneity of the disease and a lack of tumor-exclusive antigens. Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric antigen receptor (CAR)-engineered T-cells (CAR-T-cells), a therapy that has been highly successful in the treatment of B-cell leukemia and lymphoma. However, CD33 and CD123 are present on hematopoietic stem cells, and targeting with CAR-T-cells has the potential to elicit long-term myelosuppression...
October 27, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29065481/cd47-car-t-cells-effectively-kill-target-cancer-cells-and-block-pancreatic-tumor-growth
#15
Vita Golubovskaya, Robert Berahovich, Hua Zhou, Shirley Xu, Hizkia Harto, Le Li, Cheng-Chi Chao, Mike Ming Mao, Lijun Wu
CD47 is a glycoprotein of the immunoglobulin superfamily that is often overexpressed in different types of hematological and solid cancer tumors and plays important role in blocking phagocytosis, increased tumor survival, metastasis and angiogenesis. In the present report, we designed CAR (chimeric antigen receptor)-T cells that bind CD47 antigen. We used ScFv (single chain variable fragment) from mouse CD47 antibody to generate CD47-CAR-T cells for targeting different cancer cell lines. CD47-CAR-T cells effectively killed ovarian, pancreatic and other cancer cells and produced high level of cytokines that correlated with expression of CD47 antigen...
October 21, 2017: Cancers
https://www.readbyqxmd.com/read/29061641/regional-delivery-of-chimeric-antigen-receptor-engineered-t-cells-effectively-targets-her2-breast-cancer-metastasis-to-the-brain
#16
Saul J Priceman, Dileshni Tilakawardane, Brook Jeang, John P Murad, Anthony K Park, Wen-Chung Chang, Julie R Ostberg, Josh Neman, Rahul Jandial, Jana Portnow, Stephen J Forman, Christine E Brown
PURPOSE: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease...
October 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29061640/lenalidomide-enhances-the-function-of-cs1-chimeric-antigen-receptor-redirected-t-cells-against-multiple-myeloma
#17
Xiuli Wang, Miriam Walter, Ryan Urak, Lihong Weng, Christian Huynh, Laura Lim, ChingLam W Wong, Wen-Chung Chang, Sandra H Thomas, James Sanchez, Lu Yang, Christine E Brown, Flavia Pichiorri, Myo Htut, Amrita Y Krishnan, Stephen J Forman
PURPOSE: Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite considerable advances in treatment. The purpose of the study was to develop novel CARs for the treatment of MM and explore combinatorial therapy using CAR T cells and immunomodulatory drugs such as lenalidomide for increasing treatment efficacy. EXPERIMENTAL DESIGN: We redirected central memory T cells to express second-generation CAR specific for CS1 and adoptively transferred them into MM tumor-bearing mice to test their anti-MM activity...
October 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29061083/immuno-oncology-the-translational-runway-for-gene-therapy
#18
Ludger Weß, Frank Schnieders
Cancer therapy once again is experiencing a paradigm shift. This shift is based on extensive clinical experience demonstrating that cancer cannot be successfully fought by addressing single targets or pathways only. Even the combination of several neo-antigens in cancer vaccines is not sufficient for a successful, lasting tumor eradication. The focus therefore has shifted on the immune systems role in cancer and the striking abilities of cancer cells to manipulate and/or deactivate the immune system. Researchers and pharma companies have started to target the processes and cells known to support immune surveillance and the elimination of tumor cells...
October 23, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/29058636/clinical-trials-of-car-t-cells-in-china
#19
Bingshan Liu, Yongping Song, Delong Liu
Novel immunotherapeutic agents targeting tumor-site microenvironment are revolutionizing cancer therapy. Chimeric antigen receptor (CAR)-engineered T cells are widely studied for cancer immunotherapy. CD19-specific CAR-T cells, tisagenlecleucel, have been recently approved for clinical application. Ongoing clinical trials are testing CAR designs directed at novel targets involved in hematological and solid malignancies. In addition to trials of single-target CAR-T cells, simultaneous and sequential CAR-T cells are being studied for clinical applications...
October 23, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29050075/-specific-cytotoxicity-of-a-novel-her2-based-chimeric-antigen-receptor-modified-t-lymphocytes-against-her2-positive-tumor-cells
#20
H J Tang, Y Q Liu, X C Bian, H L Feng, B Gu, H Sun, C X Zuo, F Y Zhou, J Liu
Objective: To construct the third generation chimeric antigen receptor based on a novel humanized anti-HER2 H1-2 scFv, and to investigate the specific cytotoxicity of H1-2 CAR modified T lymphocytes(CAR-T) against HER2(+) tumor cells. Method: The expression cassette of the third generation CAR gene and anti-HER2 H1-2 scFv were constructed and cloned into lentivirus transfer plasmid, and then the third generation H1-2 CAR was transduced into human T lymphocytes using lentivirus.Enzyme linked immunosorbent assay was used to detect the expression of cytokines IL2, and LDH release assay was used to detect the cytotoxic effect of the H1-2 CAR-T...
October 8, 2017: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
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