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CD19 CAR

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https://www.readbyqxmd.com/read/29329591/prospects-for-chimeric-antigen-receptor-modified-t-cell-therapy-for-solid-tumors
#1
REVIEW
Erhao Zhang, Jieyi Gu, Hanmei Xu
The potential for adoptive cell immunotherapy as a treatment against cancers has been demonstrated by the remarkable response in some patients with hematological malignancies using autologous T cells endowed with chimeric antigen receptors (CARs) specific for CD19. Clinical efficacy of CAR-T cell therapy for the treatment of solid tumors, however, is rare due to physical and biochemical factors. This review focuses on different aspects of multiple mechanisms of immunosuppression in solid tumors. We characterize the current state of CAR-modified T cell therapy and summarize the various strategies to combat the immunosuppressive microenvironment of solid tumors, with the aim of promoting T cell cytotoxicity and enhancing tumor cell eradication...
January 12, 2018: Molecular Cancer
https://www.readbyqxmd.com/read/29327909/more-on-anti-cd19-car-t-cells-in-cns-diffuse-large-b-cell-lymphoma
#2
Jeremy S Abramson, Yi-Bin Chen
No abstract text is available yet for this article.
November 23, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29327908/more-on-anti-cd19-car-t-cells-in-cns-diffuse-large-b-cell-lymphoma
#3
Pierre Tiberghien, Eric Deconinck, Oliver Adotevi
No abstract text is available yet for this article.
November 23, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29315094/cd19-chimeric-antigen-receptor-t-cells-from-patients-with-chronic-lymphocytic-leukemia-display-an-elevated-ifn-%C3%AE-production-profile
#4
Isabelle Magalhaes, Ingrid Kalland, James N Kochenderfer, Anders Österborg, Michael Uhlin, Jonas Mattsson
CD19 chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated dramatic results for the treatment of B cell malignancies such as chronic lymphocytic leukemia (CLL). As T cell defects are common in patients with CLL, we compared the T cells from these patients with healthy donors (HDs), and subsequently the CD19 CAR T cells produced from patients and HDs. Despite initial differences when comparing the phenotype of circulating T cells in patients with CLL and HDs, the CD19 CAR T cells manufactured from patients' or HDs' cells showed a similar phenotype (effector memory or terminally differentiated), both were specifically activated by and killed CD19 target cells, and secreted cytokines (ie, IL-2, TNF, and IFN-γ)...
January 8, 2018: Journal of Immunotherapy
https://www.readbyqxmd.com/read/29311388/chimeric-antigen-receptor-t-cell-therapy-challenges-to-bench-to-bedside-efficacy
#5
REVIEW
Shivani Srivastava, Stanley R Riddell
Immunotherapy with T cells genetically modified to express chimeric Ag receptors (CARs) that target tumor-associated molecules have impressive efficacy in hematological malignancies. The field has now embraced the challenge of applying this approach to treat common epithelial malignancies, which make up the majority of cancer cases but evade immunologic attack by a variety of subversive mechanisms. In this study, we review the principles that have guided CAR T cell design and the extraordinary clinical results being achieved in B cell malignancies targeting CD19 with a single infusion of engineered T cells...
January 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29301772/cd19-car-t-therapy-and-sepsis-dancing-with-the-devil
#6
Lihua E Budde, John A Zaia
No abstract text is available yet for this article.
January 4, 2018: Blood
https://www.readbyqxmd.com/read/29287970/closed-system-manufacturing-of-cd19-and-dual-targeted-cd20-19-chimeric-antigen-receptor-t-cells-using-the-clinimacs-prodigy-device-at-an-academic-medical-center
#7
Fenlu Zhu, Nirav Shah, Huiqing Xu, Dina Schneider, Rimas Orentas, Boro Dropulic, Parameswaran Hari, Carolyn A Keever-Taylor
BACKGROUND AIMS: Multiple steps are required to produce chimeric antigen receptor (CAR)-T cells, involving subset enrichment or depletion, activation, gene transduction and expansion. Open processing steps that increase risk of contamination and production failure are required. This complex process requires skilled personnel and costly clean-room facilities and infrastructure. Simplified, reproducible CAR-T-cell manufacturing with reduced labor intensity within a closed-system is highly desirable for increased availability for patients...
December 26, 2017: Cytotherapy
https://www.readbyqxmd.com/read/29261129/lym-1-chimeric-antigen-receptor-t-cells-exhibit-potent-anti-tumor-effects-against-b-cell-lymphoma
#8
Long Zheng, Peisheng Hu, Brandon Wolfe, Caryn Gonsalves, Luqing Ren, Leslie A Khawli, Harvey R Kaslow, Alan L Epstein
T cells expressing chimeric antigen receptors (CARs) recognizing CD19 epitopes have produced remarkable anti-tumor effects in patients with B-cell malignancies. However, cancer cells lacking recognized epitopes can emerge, leading to relapse and death. Thus, CAR T cells targeting different epitopes on different antigens could improve immunotherapy. The Lym-1 antibody targets a conformational epitope of Human Leukocyte Antigen-antigen D Related (HLA-DR) on the surface of human B-cell lymphomas. Lym-1 CAR T cells were thus generated for evaluation of cytotoxic activity towards lymphoma cells in vitro and in vivo...
December 20, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29247018/value-in-using-car-t-cells-for-dlbcl
#9
(no author information available yet)
The phase II JULIET trial suggests that the CD19-targeting CAR T-cell therapy tisagenlecleucel produces durable responses in patients with relapsed and refractory diffuse large B-cell lymphoma. Three months after the therapy, 32% of the patients showed complete responses and 6% showed partial responses. After 6 months, those rates were 30% and 7%.
December 15, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29245005/cd19-car-t-cells
#10
Michel Sadelain
CARs are synthetic receptors that reprogram immune cells for therapeutic purposes. They comprise three canonical domains for antigen recognition, T cell activation, and costimulation. The CAR cDNA is genetically integrated in the T cell genome. Autologous CAR T cells are generated from the patient's peripheral blood T cells and expand in the recipient to eliminate the targeted tumor. To view this Bench to Bedside, open or download the PDF.
December 14, 2017: Cell
https://www.readbyqxmd.com/read/29226797/axicabtagene-ciloleucel-car-t-cell-therapy-in-refractory-large-b-cell-lymphoma
#11
Sattva S Neelapu, Frederick L Locke, Nancy L Bartlett, Lazaros J Lekakis, David B Miklos, Caron A Jacobson, Ira Braunschweig, Olalekan O Oluwole, Tanya Siddiqi, Yi Lin, John M Timmerman, Patrick J Stiff, Jonathan W Friedberg, Ian W Flinn, Andre Goy, Brian T Hill, Mitchell R Smith, Abhinav Deol, Umar Farooq, Peter McSweeney, Javier Munoz, Irit Avivi, Januario E Castro, Jason R Westin, Julio C Chavez, Armin Ghobadi, Krishna V Komanduri, Ronald Levy, Eric D Jacobsen, Thomas E Witzig, Patrick Reagan, Adrian Bot, John Rossi, Lynn Navale, Yizhou Jiang, Jeff Aycock, Meg Elias, David Chang, Jeff Wiezorek, William Y Go
Background In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy. Methods In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine...
December 10, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29226764/chimeric-antigen-receptor-t-cells-in-refractory-b-cell-lymphomas
#12
Stephen J Schuster, Jakub Svoboda, Elise A Chong, Sunita D Nasta, Anthony R Mato, Özlem Anak, Jennifer L Brogdon, Iulian Pruteanu-Malinici, Vijay Bhoj, Daniel Landsburg, Mariusz Wasik, Bruce L Levine, Simon F Lacey, Jan J Melenhorst, David L Porter, Carl H June
Background Patients with diffuse large B-cell lymphoma or follicular lymphoma that is refractory to or that relapses after immunochemotherapy and transplantation have a poor prognosis. High response rates have been reported with the use of T cells modified by chimeric antigen receptor (CAR) that target CD19 in B-cell cancers, although data regarding B-cell lymphomas are limited. Methods We used autologous T cells that express a CD19-directed CAR (CTL019) to treat patients with diffuse large B-cell lymphoma or follicular lymphoma that had relapsed or was refractory to previous treatments...
December 10, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29212954/inhibition-of-akt-signaling-uncouples-t-cell-differentiation-from-expansion-for-receptor-engineered-adoptive-immunotherapy
#13
Christopher A Klebanoff, Joseph G Crompton, Anthony J Leonardi, Tori N Yamamoto, Smita S Chandran, Robert L Eil, Madhusudhanan Sukumar, Suman K Vodnala, Jinhui Hu, Yun Ji, David Clever, Mary A Black, Devikala Gurusamy, Michael J Kruhlak, Ping Jin, David F Stroncek, Luca Gattinoni, Steven A Feldman, Nicholas P Restifo
Adoptive immunotherapies using T cells genetically redirected with a chimeric antigen receptor (CAR) or T cell receptor (TCR) are entering mainstream clinical practice. Despite encouraging results, some patients do not respond to current therapies. In part, this phenomenon has been associated with infusion of reduced numbers of early memory T cells. Herein, we report that AKT signaling inhibition is compatible with CAR and TCR retroviral transduction of human T cells while promoting a CD62L-expressing central memory phenotype...
December 7, 2017: JCI Insight
https://www.readbyqxmd.com/read/29207878/cd20-cd19-bispecific-car-t-cells-for-the-treatment-of-b-cell-malignancies
#14
Alexandra Martyniszyn, Ann-Christin Krahl, Maya C André, Andreas A Hombach, Hinrich Abken
The treatment of leukemia/lymphoma by chimeric antigen receptor (CAR) redirected T cells with specificity for CD19 induced complete remissions in the majority of patients with a realistic hope for cure. However, recent follow-up data revealed a substantial risk of relapse through leukemic cells which lack the CAR targeted antigen. In this situation a bispecific CAR with binding domains for CD19 and CD20 is aimed at recognizing also leukemic cells with only one cognate antigen. The anti-CD20-CD19 bispecific CAR induced a full T cell response upon engagement of CD19 or CD20 on target cells showing a true "OR" gate recognition in redirecting T cell activation...
December 5, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/29176353/new-developments-in-immunotherapy-for-pediatric-leukemia
#15
Jessica B Foster, Shannon L Maude
PURPOSE OF REVIEW: Immunotherapy for the treatment of cancer has advanced at a tremendous pace over the last decade. In this review, we provide an overview of recent progress in immunotherapy for the treatment of leukemia, focusing on antibody-drug conjugates (ADC), bi-specific T-cell engagers (BiTE), and chimeric antigen receptor (CAR) T cells. RECENT FINDINGS: Ongoing clinical trials of CAR T cells directed against CD19 have produced complete remission rates as high as 93%, prompting global multicenter phase 2 trials and the first FDA approval of a CAR T-cell therapy...
February 2018: Current Opinion in Pediatrics
https://www.readbyqxmd.com/read/29176334/preclinical-optimization-of-a-cd20-specific-chimeric-antigen-receptor-vector-and-culture-conditions
#16
Sang Yun Lee, Philip Olsen, Dong Hoon Lee, Aimee L Kenoyer, Lihua E Budde, Shyril O'Steen, Damian J Green, Shelly Heimfeld, Michael C Jensen, Stanley R Riddell, Oliver W Press, Brian G Till
Chimeric antigen receptor (CAR)-based adoptive T-cell therapy is a highly promising treatment for lymphoid malignancies, and CD20 is an ideal target antigen. We previously developed a lentiviral construct encoding a third generation CD20-targeted CAR but identified several features that required additional optimization before clinical translation. We describe here several improvements, including replacement of the immunogenic murine antigen-binding moiety with a fully human domain, streamlining the transgene insert to enhance lentiviral titers, modifications to the extracellular IgG spacer that abrogate nonspecific activation resulting from binding to Fc receptors, and evaluation of CD28, 4-1BB, or CD28 and 4-1BB costimulatory domains...
November 23, 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/29174320/-prerequisite-for-hematopoietic-cellular-therapy-programs-to-set-up-chimeric-antigen-receptor-t-cell-therapy-car-t-cells-guidelines-from-the-french-speaking-society-of-bone-marrow-transplantation-and-cellular-therapy-sfgm-tc
#17
Ibrahim Yakoub-Agha, Christophe Ferrand, Yves Chalandon, Caroline Ballot, Cristina Castilla Llorente, Marina Deschamps, Jordan Gauthier, Myriam Labalette, Jérôme Larghero, Camille Maheux, Anne-Sophie Moreau, Pauline Varlet, Marie-Odile Pétillon, Marine Pinturaud, Marie Thérèse Rubio, Christian Chabannon
CAR T-cells are autologous or allogeneic human lymphocytes that are genetically engineered to express a chimeric antigen receptor targeting an antigen expressed on tumor cells such as CD19. CAR T-cells represent a new class of medicinal products, and belong to the broad category of Advanced Therapy Medicinal Products (ATMPs), as defined by EC Regulation 2007-1394. Specifically, they are categorized as gene therapy medicinal products. Although CAR T-cells are cellular therapies, the organization for manufacturing and delivery is far different from the one used to deliver hematopoietic cell grafts, for different reasons including their classification as medicinal products...
November 23, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/29167392/tcr-engagement-negatively-affects-cd8-but-not-cd4-car-t-cell-expansion-and-leukemic-clearance
#18
Yinmeng Yang, M Eric Kohler, Christopher D Chien, Christopher T Sauter, Elad Jacoby, Chunhua Yan, Ying Hu, Kelsey Wanhainen, Haiying Qin, Terry J Fry
Chimeric antigen receptor (CAR)-expressing T cells induce durable remissions in patients with relapsed/refractory B cell malignancies. CARs are synthetic constructs that, when introduced into mature T cells, confer a second, non-major histocompatibility complex-restricted specificity in addition to the endogenous T cell receptor (TCR). The implications of TCR activation on CAR T cell efficacy has not been well defined. Using an immunocompetent, syngeneic murine model of CD19-targeted CAR T cell therapy for pre-B cell acute lymphoblastic leukemia in which the CAR is introduced into T cells with known TCR specificity, we demonstrate loss of CD8 CAR T cell efficacy associated with T cell exhaustion and apoptosis when TCR antigen is present...
November 22, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29166735/-the-specific-cytotoxicities-of-chimeric-antigen-receptor-engineered-t-cells-on-different-lymphomas
#19
R Zhang, Q Deng, S N Sui, X Jin, M F Zhao
Objective: To investigate the specific cytotoxicities of the second and third generations of chimeric antigen receptor (CAR) -engineered T cells (CAR-T) on different lymphomas. Methods: CAR-Ts were prepared by lentivirus packaging and infection of T cells. CCK-8, ELISA and Lactate dehydrogenase cytotoxicity assay were applied to detect the proliferation capacity, the secretion level of inflammatory factor and the specific cytotoxicity. Flow cytometry assay showed the specific cytotoxicity and residual level of CAR-T in lymphomas of treated mice...
October 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/29166240/more-on-anti-cd19-car-t-cells-in-cns-diffuse-large-b-cell-lymphoma
#20
LETTER
Jeremy S Abramson, Yi-Bin Chen
New England Journal of Medicine, Volume 377, Issue 21, Page 2101-2102, November 2017.
November 23, 2017: New England Journal of Medicine
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