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CD19 CAR

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https://www.readbyqxmd.com/read/29157295/single-cell-multiplexed-cytokine-profiling-of-cd19-car-t-cells-reveals-a-diverse-landscape-of-polyfunctional-antigen-specific-response
#1
Qiong Xue, Emily Bettini, Patrick Paczkowski, Colin Ng, Alaina Kaiser, Timothy McConnell, Olja Kodrasi, Máire F Quigley, James Heath, Rong Fan, Sean Mackay, Mark E Dudley, Sadik H Kassim, Jing Zhou
BACKGROUND: It remains challenging to characterize the functional attributes of chimeric antigen receptor (CAR)-engineered T cell product targeting CD19 related to potency and immunotoxicity ex vivo, despite promising in vivo efficacy in patients with B cell malignancies. METHODS: We employed a single-cell, 16-plex cytokine microfluidics device and new analysis techniques to evaluate the functional profile of CD19 CAR-T cells upon antigen-specific stimulation. CAR-T cells were manufactured from human PBMCs transfected with the lentivirus encoding the CD19-BB-z transgene and expanded with anti-CD3/anti-CD28 coated beads...
November 21, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29156206/cytokine-release-syndrome-who-is-at-risk-and-how-to-treat
#2
REVIEW
Noelle Frey
T-cell engaging therapies such as blinatumomab and anti-CD19 chimeric antigen receptor (CAR) T cells have revolutionized our approach to patients with relapsed and refractory acute lymphoblastic leukemia (ALL). However, the immune activation responsible for high remission rates is also responsible for the unique treatment-related toxicity of cytokine release syndrome (CRS). The clinical signs of CRS include fever, hemodynamic instability, and capillary leak, which correlate with T-cell activation and elevated cytokine levels...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29155426/cd22-targeted-car-t-cells-induce-remission-in-b-all-that-is-naive-or-resistant-to-cd19-targeted-car-immunotherapy
#3
Terry J Fry, Nirali N Shah, Rimas J Orentas, Maryalice Stetler-Stevenson, Constance M Yuan, Sneha Ramakrishna, Pamela Wolters, Staci Martin, Cindy Delbrook, Bonnie Yates, Haneen Shalabi, Thomas J Fountaine, Jack F Shern, Robbie G Majzner, David F Stroncek, Marianna Sabatino, Yang Feng, Dimiter S Dimitrov, Ling Zhang, Sang Nguyen, Haiying Qin, Boro Dropulic, Daniel W Lee, Crystal L Mackall
Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent effects in relapsed and/or refractory pre-B cell acute lymphoblastic leukemia (B-ALL), but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed in most cases of B-ALL and is usually retained following CD19 loss. We report results from a phase 1 trial testing a new CD22-targeted CAR (CD22-CAR) in 21 children and adults, including 17 who were previously treated with CD19-directed immunotherapy...
November 20, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29147628/trial-watch-adoptively-transferred-cells-for-anticancer-immunotherapy
#4
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
#5
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/29119551/chimeric-antigen-receptor-transduced-t-cells-tuning-up-for-the-next-generation
#6
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
#7
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/29107016/chimeric-antigen-receptor-car-t-cell-therapy-for-thoracic-malignancies
#8
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/29076142/donor-derived-cd19-targeted-t-cell-infusion-induces-minimal-residual-disease-negative-remission-in-relapsed-b-cell-acute-lymphoblastic-leukaemia-with-no-response-to-donor-lymphocyte-infusions-after-haploidentical-haematopoietic-stem-cell-transplantation
#9
Yuhong Chen, Yifei Cheng, Pan Suo, Chenhua Yan, Yu Wang, Yao Chen, Wei Han, Lanping Xu, Xiaohui Zhang, Kaiyan Liu, Lungji Chang, Lei Xiao, Xiaojun Huang
Relapse is a common cause of failure in patients with B-cell acute lymphoblastic leukaemia (B-ALL) after haploidentical haematopoietic stem cell transplantation (haplo-HSCT), and non-responders to donor lymphoblastic infusion after HSCT have a very poor prognosis. Although donor-derived CD19-directed chimeric antigen receptor-modified (CAR) T cells can potentially cure leukaemia, their effectiveness and safety have not been confirmed in relapsed B-ALL cases after haplo-HSCT. Between January 2015 and January 2017, two and four patients each received one and two infusions of CAR T cells from haplo-HSCT donors...
October 26, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/29058636/clinical-trials-of-car-t-cells-in-china
#10
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/29058502/axicabtagene-ciloleucel-a-first-in-class-car-t-cell-therapy-for-aggressive-nhl
#11
Zachary J Roberts, Marc Better, Adrian Bot, Margo R Roberts, Antoni Ribas
The development of clinically functional chimeric antigen receptor (CAR) T cell therapy is the culmination of multiple advances over the last three decades. Axicabtagene ciloleucel (formerly KTE-C19) is an anti-CD19 CAR T cell therapy in development for patients with refractory diffuse large B cell lymphoma (DLBCL), including transformed follicular lymphoma (TFL) and primary mediastinal B cell lymphoma (PMBCL). Axicabtagene ciloleucel is manufactured from patients' own peripheral blood mononuclear cells (PBMC) during which T cells are engineered to express a CAR that redirects them to recognize CD19-expressing cells...
October 23, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29050700/the-what-when-and-how-of-car-t-cell-therapy-for-all
#12
REVIEW
Noelle Frey
Chimeric Antigen Receptor (CAR) T cells that have been engineered to target CD19 have shown great promise in patients with relapsed and refractory B cell acute lymphocytic leukemia with remission rates of 70-90%. Some remissions have successfully bridged patients to a curable allogeneic stem cell transplant, some responses have been durable without further treatment, and some patients have achieved durable remissions for relapsed ALL after allogeneic stem cell transplant. Cytokine release syndrome, correlating with the in vivo activation and expansion of T cells, and neurologic toxicity are the most significant side effects and approaches to better understand and manage these events are the subject of ongoing clinical trials...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050693/how-should-we-treat-older-adults-with-ph-adult-all-and-what-novel-approaches-are-being-investigated
#13
REVIEW
Matthew J Wieduwilt
Treatment of older patients with Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia presents unique challenges. Advanced age, comorbidities, high treatment-related death rates with traditional chemotherapy, and relapse combine to yield poor survival. Reduced-intensity induction with BCR-ABL1 targeted tyrosine kinase inhibitors (TKIs) and corticosteroids yields CR rates 96-100% with no induction mortality but relapse is nearly certain without effective consolidation. Few clinical trials provide guidance on optimal consolidation for older Ph+ ALL...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29046826/incorporation-of-functional-elements-enhances-the-antitumor-capacity-of-car-t-cells
#14
REVIEW
Le Qin, Ruocong Zhao, Peng Li
As chimeric antigen receptor (CAR) T cells have displayed an unprecedented efficacy in the treatment of CD19-positive malignances, it is believed that this cell therapy will be a milestone in the history of mankind's conquering of cancer. However, there are some issues that restrict CAR T cells from reaching their optimal anti-tumor capacity, especially in the treatment of solid tumors. Inhibitory cytokines, immune checkpoint molecules, hypoxia and other adverse factors have been reported to be involved in this process...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/29043880/concurrent-therapy-of-chronic-lymphocytic-leukemia-and-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-utilizing-cd19-targeted-car-t-cells
#15
Mark B Geyer, Shwetha H Manjunath, Andrew G Evans, Jae H Park, Marco L Davila, Corey S Cutler, Xiuyan Wang, Yongzeng Wang, Brigitte Senechal, Isabelle Rivière, Michel Sadelain, Jane L Liesveld, Renier J Brentjens
No abstract text is available yet for this article.
October 18, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29039115/genome-editing-technologies-in-adoptive-t-cell-immunotherapy-for-cancer
#16
REVIEW
Nathan Singh, Junwei Shi, Carl H June, Marco Ruella
PURPOSE OF REVIEW: In this review, we discuss the most recent developments in gene-editing technology and discuss their application to adoptive T cell immunotherapy. RECENT FINDINGS: Engineered T cell therapies targeting cancer antigens have demonstrated significant efficacy in specific patient populations. Most impressively, CD19-directed chimeric antigen receptor T cells (CART19) have led to impressive responses in patients with B-cell leukemia and lymphoma. CTL019, or KYMRIAH™ (tisagenlecleucel), a CD19 CAR T cell product developed by Novartis and the University of Pennsylvania, was recently approved for clinical use by the Food and Drug Administration, representing a landmark in the application of adoptive T cell therapies...
October 16, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/29038338/infectious-complications-of-cd19-targeted-chimeric-antigen-receptor-modified-t-cell-immunotherapy
#17
Joshua A Hill, Daniel Li, Kevin A Hay, Margaret L Green, Sindhu Cherian, Xueyan Chen, Stanley R Riddell, David G Maloney, Michael Boeckh, Cameron J Turtle
Lymphodepletion chemotherapy with CD19-targeted chimeric antigen receptor-modified T (CAR-T) cell immunotherapy is a novel treatment for refractory or relapsed B cell malignancies. However, infectious complications of this approach have not been systematically studied. We evaluated infection events occurring between days 0-28 and 29-90 in 133 patients treated with CD19 CAR-T cells in a phase 1/2 study (https://clinicaltrials.gov/ct2/show/NCT01865617). We used multivariable Poisson and Cox regression to evaluate pre- and post-treatment risk factors for infection, respectively...
October 16, 2017: Blood
https://www.readbyqxmd.com/read/29032736/coccidioidomycosis-immunoglobulin-deficiency-safety-challenges-with-car-t-cells-therapy-for-relapsed-lymphoma
#18
Umar Zahid, Al-Aman Shaukat, Nida Hassan, Faiz Anwer
Treatment of patients with relapsed or refractory lymphoma may require allogenic hematopoietic stem cell transplant (HSCT), but treatment of post-transplant relapse disease remains very challenging. Donor lymphocyte infusion and blinatumomab have been used with limited success for the treatment of relapse. Initial data on donor-derived CAR T cells has shown this modality to be safe and highly effective in various hematological malignancies. We present a case of a patient with highly refractory, transformed follicular lymphoma who failed both autologous and allogenic HSCT...
October 2017: Immunotherapy
https://www.readbyqxmd.com/read/29032264/building-a-safer-and-faster-car-seatbelts-airbags-and-crispr
#19
REVIEW
Miguel-Angel Perales, Partow Kebriaei, Leslie S Kean, Michel Sadelain
Therapeutic T cell engineering has recently garnered widespread interest owing to the success of CD19 (Chimeric Antigen Receptor) CAR therapy. CARs are synthetic receptors for antigen that redirect the specificity and reprogram the function of the T cells in which they are genetically introduced. CARs targeting CD19, a cell surface molecule found in most leukemias and lymphomas, have yielded high remission rates in patients with chemorefractory, relapsed disease, including acute lymphoblastic leukemia, chronic lymphocytic leukemia and non-Hodgkin lymphoma...
October 12, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29025771/endothelial-activation-and-blood-brain-barrier-disruption-in-neurotoxicity-after-adoptive-immunotherapy-with-cd19-car-t-cells
#20
Juliane Gust, Kevin A Hay, Laïla-Aïcha Hanafi, Daniel Li, David Myerson, Luis F Gonzalez-Cuyar, Cecilia Yeung, W Conrad Liles, Mark Wurfel, Jose A Lopez, Junmei Chen, Dominic Chung, Susanna Harju-Baker, Tahsin Özpolat, Kathleen R Fink, Stanley R Riddell, David G Maloney, Cameron J Turtle
Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19(+) cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability...
October 12, 2017: Cancer Discovery
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