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Car t-cell therapy

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https://www.readbyqxmd.com/read/29147628/trial-watch-adoptively-transferred-cells-for-anticancer-immunotherapy
#1
REVIEW
Carole Fournier, François Martin, Laurence Zitvogel, Guido Kroemer, Lorenzo Galluzzi, Lionel Apetoh
Immunotherapies aimed at strengthening immune effector responses against malignant cells are growing at exponential rates. Alongside, the impressive benefits obtained by patients with advanced melanoma who received adoptively transferred tumor-infiltrating lymphocytes (TILs) have encouraged the scientific community to pursue adoptive cell transfer (ACT)-based immunotherapy. ACT involves autologous or allogenic effector lymphocytes that are generally obtained from the peripheral blood or resected tumors, expanded and activated ex vivo, and administered to lymphodepleted patients...
2017: Oncoimmunology
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/29123516/avidity-and-bystander-suppressive-capacity-of-human-regulatory-t-cells-expressing-de-novo-autoreactive-t-cell-receptors-in-type-1-diabetes
#6
Wen-I Yeh, Howard R Seay, Brittney Newby, Amanda L Posgai, Filipa Botelho Moniz, Aaron Michels, Clayton E Mathews, Jeffrey A Bluestone, Todd M Brusko
The ability to alter antigen specificity by T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene transfer has facilitated personalized cellular immune therapies in cancer. Inversely, this approach can be harnessed in autoimmune settings to attenuate inflammation by redirecting the specificity of regulatory T cells (Tregs). Herein, we demonstrate efficient protocols for lentiviral gene transfer of TCRs that recognize type 1 diabetes-related autoantigens with the goal of tissue-targeted induction of antigen-specific tolerance to halt β-cell destruction...
2017: Frontiers in Immunology
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/29118234/emerging-role-of-car-t-cells-in-non-hodgkin-s-lymphoma
#8
REVIEW
Mauro P Avanzi, Renier J Brentjens
Adoptive T-cell therapy with chimeric antigen receptor T cells (CAR-Ts) has produced impressive clinical responses among patients with B-cell malignancies, and several groups have published positive results using anti-CD19 CAR-Ts for the treatment of B-cell acute lymphoblastic leukemia. Recently, new data from clinical trials have demonstrated the benefits of CAR-T therapy in the non-Hodgkin's lymphoma (NHL) setting. This review describes some of the most recent and promising advances in engineered T-cell therapy, with particular emphasis on the clinical benefits of NHL treatment...
November 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29113977/fda-approves-second-car-t-cell-therapy
#9
(no author information available yet)
The FDA approved the chimeric antigen receptor T-cell therapy axicabtagene ciloleucel, making it the second such treatment for blood cancers in the United States. The therapy is indicated for adults with certain non-Hodgkin lymphomas who have tried at least two other treatments.
November 7, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29107016/chimeric-antigen-receptor-car-t-cell-therapy-for-thoracic-malignancies
#10
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/29106400/the-activated-conformation-of-integrin-%C3%AE-7-is-a-novel-multiple-myeloma-specific-target-for-car-t-cell-therapy
#11
Naoki Hosen, Yukiko Matsunaga, Kana Hasegawa, Hiroshi Matsuno, Yuki Nakamura, Mio Makita, Kouki Watanabe, Mikako Yoshida, Kei Satoh, Soyoko Morimoto, Fumihiro Fujiki, Hiroko Nakajima, Jun Nakata, Sumiyuki Nishida, Akihiro Tsuboi, Yoshihiro Oka, Masahiro Manabe, Hiroyoshi Ichihara, Yasutaka Aoyama, Atsuko Mugitani, Takafumi Nakao, Masayuki Hino, Ryosuke Uchibori, Keiya Ozawa, Yoshihiro Baba, Seitaro Terakura, Naoki Wada, Eiichi Morii, Junichi Nishimura, Kiyoshi Takeda, Yusuke Oji, Haruo Sugiyama, Junichi Takagi, Atsushi Kumanogoh
Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened >10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin β7 molecules. The MMG49 epitope, in the N-terminal region of the β7 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation...
November 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29105517/car-t-cell-therapy-for-multiple-myeloma-where-are-we-now-and-where-are-we-headed
#12
Arnab Ghosh, Sham Mailankody, Sergio A Giralt, C Ola Landgren, Eric L Smith, Renier J Brentjens
While recent progress has been made in the management of multiple myeloma, it remains a highly fatal malignancy especially among patients with relapsed-refractory disease. Immunotherapy with adoptive T cells targeting myeloma-associated antigens are at various stages of development and have brought about a new hope for cure. This is a review on the emerging field of adoptively transferred engineered T cell based approaches, with an in-depth focus on chimeric antigen receptors (CAR) targeting multiple myeloma...
November 6, 2017: Leukemia & Lymphoma
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
#13
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/29103317/anticancer-cellular-immunotherapies-derived-from-umbilical-cord-blood
#14
Katalin Balassa, Vanderson Rocha
Introduction The lack of highly effective drugs in many malignancies has prompted scientific interest in the development of alternative treatment strategies. Cellular immunotherapy involving the adoptive transfer of immune cells that potently recognize and eliminate malignantly transformed cells has become a promising new tool in the anticancer armory. Studies suggest that the unique biological properties of umbilical cord blood (UCB) cells could precipitate enhanced anticancer activity; hence, UCB could be an optimal source for immunotherapy with the potential to provide products with "off-the-shelf" availability...
November 6, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29089311/slamf7-car-t-cells-eliminate-myeloma-and-confer-selective-fratricide-of-slamf7-normal-lymphocytes
#15
Tea Gogishvili, Sophia Danhof, Sabrina Prommersberger, Julian Rydzek, Martin Schreder, Christian Brede, Hermann Einsele, Michael Hudecek
SLAMF7 is under intense investigation as a target for immunotherapy in multiple myeloma. Here, we redirected the specificity of T-cells to SLAMF7 through expression of a chimeric antigen receptor (CAR) derived from the huLuc63 antibody (Elotuzumab), and demonstrate that SLAMF7-CAR T-cells prepared from patients and healthy donors confer potent antimyeloma reactivity. We confirmed uniform, high-level expression of SLAMF7 on malignant plasma cells in previously untreated and in relapsed/refractory (R/R) myeloma patients who had received prior treatment with proteasome-inhibitors and immunomodulatory agents (IMiDs)...
October 31, 2017: Blood
https://www.readbyqxmd.com/read/29080982/the-progress-and-current-status-of-immunotherapy-in-acute-myeloid-leukemia
#16
REVIEW
Dan Yang, Xiuqun Zhang, Xuezhong Zhang, Yanli Xu
Recently, there has been remarkable progress in basic and preclinical studies of acute myeloid leukemia (AML). The improved outcomes of AML can largely be attributed to advances in supportive care and hematopoietic cell transplantation as opposed to conventional chemotherapy. However, as the 5-year survival rate remains low due to a high incidence of relapse, novel and effective treatments are urgently needed. Increasing attention is focusing on identifying suitable immunotherapeutic strategies for AML. Here, we describe the immunological features, mechanisms of immune escape, and recent progress in immunotherapy for AML...
October 28, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/29077054/development-of-a-chimeric-antigen-receptor-targeting-c-type-lectin-like-molecule-1-for-human-acute-myeloid-leukemia
#17
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/29073235/src-family-kinases-negatively-regulate-nfat-signaling-in-resting-human-t-cells
#18
Alan Baer, Winston Colon-Moran, Jinhua Xiang, Jack T Stapleton, Nirjal Bhattarai
T cell signaling is required for activation of both natural and therapeutic T cells including chimeric antigen receptor (CAR) T cells. Identification of novel factors and pathways regulating T cell signaling may aid in development of effective T cell therapies. In resting human T cells, the majority of Src-family of tyrosine kinases (SFKs) are inactive due to phosphorylation of a conserved carboxy-terminal tyrosine residue. Recently, a pool of enzymatically active SFKs has been identified in resting T cells; however, the significance of these is incompletely understood...
2017: PloS One
https://www.readbyqxmd.com/read/29068298/novartis-s-kymriah-harnessing-immune-system-comes-with-worry-about-reining-in-costs
#19
Thomas Morrow
FDA approval of the CAR T-cell therapy for leukemia could usher in an era of genetically engineered, individually tailored immunotherapies. But tap those brakes. Long-term results are in short supply-and there's that $475,000 price tag. Or is it a $750,000 price tag?
October 2017: Managed Care
https://www.readbyqxmd.com/read/29061640/lenalidomide-enhances-the-function-of-cs1-chimeric-antigen-receptor-redirected-t-cells-against-multiple-myeloma
#20
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
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