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Chimeric Antigen Receptor T cells

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https://www.readbyqxmd.com/read/29222400/nkg2d-based-car-t-cells-and-radiotherapy-exert-synergistic-efficacy-in-glioblastoma
#1
Tobias Weiss, Michael Weller, Matthias Guckenberger, Charles L Sentman, Patrick Roth
Chimeric antigen receptor (CAR) T cell therapy is an emerging immunotherapy against several malignancies including glioblastoma, the most common and most aggressive malignant primary brain tumor in adults. The challenges in solid tumor immunotherapy comprise heterogenously expressed tumor target antigens and restricted trafficking of CAR T cells to and impaired long-term persistence at the tumor site, as well as the unaddressed integration of CAR T cell therapy into conventional anti-cancer treatments. We addressed these questions using a NKG2D-based chimeric antigen receptor construct (chNKG2D) in fully immunocompetent orthotopic glioblastoma mouse models...
December 8, 2017: Cancer Research
https://www.readbyqxmd.com/read/29222325/cells-to-prevent-treat-relapse-following-allogeneic-stem-cell-transplantation
#2
REVIEW
Andrew C Dietz, Alan S Wayne
Relapse of cancer remains one of the primary causes of treatment failure and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). A multitude of approaches have been used in the management of posttransplant relapse. This review focuses on recent data with cellular therapies designed to treat or prevent posttransplant relapse of hematologic malignancies, although many of these therapeutic approaches also have applications to solid tumors and in the nontransplant setting. Currently available cell therapies include second transplant, natural killer cells, monocyte-derived dendritic cell vaccines, and lymphocytes via donor lymphocyte infusion, antigen-primed cytotoxic T lymphocytes, cytokine-induced killer cells, marrow-infiltrating lymphocytes, and chimeric antigen receptor T cells...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29222313/developing-t-cell-therapies-for-lymphoma-without-receptor-engineering
#3
REVIEW
Melanie Grant, Catherine M Bollard
T-cell therapy has emerged from the bench for the treatment of patients with lymphoma. Responses to T-cell therapeutics are regulated by multiple factors, including the patient's immune system status and disease stage. Outside of engineering of chimeric antigen receptors and artificial T-cell receptors, T-cell therapy can be mediated by ex vivo expansion of antigen-specific T cells targeting viral and/or nonviral tumor-associated antigens. These approaches are contributing to enhanced clinical responses and overall survival...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29222264/incorporation-of-nonchemotherapeutic-agents-in-pediatric-acute-lymphoblastic-leukemia
#4
REVIEW
Lewis B Silverman
With current available therapies, the prognosis for most children and adolescents with acute lymphoblastic leukemia (ALL) is favorable. However, the multiagent chemotherapy regimens used to treat newly diagnosed patients are associated with many acute and long-term complications, and therapy for relapsed disease is intensive and suboptimally effective. Over the last decade, several nonchemotherapeutic approaches have been evaluated, with the goal of identifying more effective, less toxic therapies that can be used in conjunction with, or even replace, current regimens...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29220291/emerging-targeted-and-immune-based-therapies-in-sarcoma
#5
Seth M Pollack, Matthew Ingham, Matthew B Spraker, Gary K Schwartz
Soft tissue and bone sarcomas are malignancies of mesenchymal origin, and more than 50 subtypes are defined. For most sarcomas, locally advanced or unresectable disease is still treated with cytotoxic chemotherapy. Recently, our understanding of subtype-specific cancer biology has expanded, and it has revealed distinct molecular alterations responsible for tumor initiation and progression. These findings have motivated the development of targeted therapies that are being evaluated in subtype-specific or biomarker-driven clinical trials...
December 8, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29217780/from-transplant-to-novel-cellular-therapies-in-multiple-myeloma-emn-guidelines-and-future-perspectives
#6
Francesca Gay, Monika Engelhardt, Evangelos Terpos, Ralph Wäsch, Luisa Giaccone, Holger W Auner, Jo Caers, Martin Gramatzki, Niels van de Donk, Stefania Oliva, Elena Zamagni, Laurent Garderet, Christian Straka, Roman Hajek, Heinz Ludwig, Hermann Einsele, Meletios Dimopoulos, Mario Boccadoro, Nicolaus Kröger, Michele Cavo, Hartmut Goldschmidt, Benedetto Bruno, Pieter Sonneveld
Survival of myeloma patients has greatly improved with the use of autologous stem cell transplantation and novel agents, such as proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. Compared to bortezomib- and lenalidomide-based regimens alone, the addition of high-dose melphalan followed by autologous transplantation significantly improves progression-free survival; although an overall survival benefit was not observed in all trials. Moreover, follow-up of recent trials is still too short to show any difference in survival...
December 7, 2017: Haematologica
https://www.readbyqxmd.com/read/29212954/inhibition-of-akt-signaling-uncouples-t-cell-differentiation-from-expansion-for-receptor-engineered-adoptive-immunotherapy
#7
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/29209782/advances-in-immunotherapeutic-research-for-glioma-therapy
#8
REVIEW
Jeremy Tetsuo Miyauchi, Stella E Tsirka
Gliomas are primary malignancies of the brain. Tumors are staged based on malignancy, nuclear atypia, and infiltration of the surrounding brain parenchyma. Tumors are often diagnosed once patients become symptomatic, at which time the lesion is sizable. Glioblastoma (grade IV glioma) is highly aggressive and difficult to treat. Most tumors are diagnosed de novo. The gold standard of therapy, implemented over a decade ago, consists of fractionated radiotherapy and temozolomide, but unfortunately, chemotherapeutic resistance arises...
December 5, 2017: Journal of Neurology
https://www.readbyqxmd.com/read/29209570/car-t-cell-immunotherapy-of-met-expressing-malignant-mesothelioma
#9
Thivyan Thayaparan, Roseanna M Petrovic, Daniela Y Achkova, Tomasz Zabinski, David M Davies, Astero Klampatsa, Ana C Parente-Pereira, Lynsey M Whilding, Sjoukje Jc van der Stegen, Natalie Woodman, Michael Sheaff, Jennifer R Cochran, James F Spicer, John Maher
Mesothelioma is an incurable cancer for which effective therapies are required. Aberrant MET expression is prevalent in mesothelioma, although targeting using small molecule-based therapeutics has proven disappointing. Chimeric antigen receptors (CARs) couple the HLA-independent binding of a cell surface target to the delivery of a tailored T-cell activating signal. Here, we evaluated the anti-tumor activity of MET re-targeted CAR T-cells against mesothelioma. Using immunohistochemistry, MET was detected in 67% of malignant pleural mesotheliomas, most frequently of epithelioid or biphasic subtype...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29208775/cns-endothelial-cell-activation-emerges-as-a-driver-of-car-t-cell-associated-neurotoxicity
#10
COMMENT
Crystal L Mackall, David B Miklos
<b/> Central nervous system (CNS) toxicity associated with chimeric antigen receptor-based therapeutics has emerged as a significant cause of morbidity and mortality, and insights into the pathophysiology of this syndrome have been lacking. A new study provides evidence that cytokine-induced CNS endothelial cell activation leading to disruption of the blood-brain barrier plays an early and critical role in this phenomenon. These insights provide new opportunities for targeted therapeutic interventions to modulate endothelial cell activation...
December 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29207878/cd20-cd19-bispecific-car-t-cells-for-the-treatment-of-b-cell-malignancies
#11
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/29207115/current-status-and-future-prospects-of-the-strategy-of-combining-car%C3%A2-t-with-pd%C3%A2-1-blockade-for-antitumor-therapy-review
#12
Jinjing Xu, Qing Zhang, Kang Tian, Haiyu Wang, Hong Yin, Junnian Zheng
The immune system serves an important role in controlling and eradicating malignant cells. Immunotherapy for treating tumors has received much attention in recent years due to its marked effect. There are two approaches which currently lead this field: Chimeric antigen receptor‑modified T‑cell immunotherapy (CAR‑T) and programmed cell death protein-1 blockade (PD‑1 blockade). CAR‑T has emerged as a promising regimen for the treatment of a range of types of cancer, including chronic lymphoid leukemia and neuroblastoma, with studies of long term remission in certain patients...
November 22, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29204156/sp17-protein-expression-and-major-histocompatibility-class-i-and-ii-epitope-presentation-in-diffuse-large-b-cell-lymphoma-patients
#13
Kamel Ait-Tahar, Amanda P Anderson, Martin Barnardo, Graham P Collins, Chris S R Hatton, Alison H Banham, Karen Pulford
Improved therapies are urgently needed for patients with diffuse large B cell lymphoma (DLBCL). Success using immune checkpoint inhibitors and chimeric antigen receptor T cell technology has fuelled demand for validated cancer epitopes. Immunogenic cancer testis antigens (CTAs), with their widespread expression in many tumours but highly restricted normal tissue distribution, represent attractive immunotherapeutic targets that may improve treatment options for DLBCL and other malignancies. Sperm protein 17 (Sp17), a CTA reported to be immunogenic in ovarian cancer and myeloma patients, is expressed in DLBCL...
2017: Advances in Hematology
https://www.readbyqxmd.com/read/29197675/japanese-recipients-who-receive-hla-matched-hematopoietic-cell-transplantation-for-their-myeloid-leukemia-have-an-advantage-to-prevent-recurrence-if-they-have-homozygous-hla-c1
#14
Nobuyoshi Arima, Junya Kanda, Junji Tanaka, Toshio Yabe, Yasuo Morishima, Sung-Won Kim, Yuho Najima, Yukiyasu Ozawa, Tetsuya Eto, Heiwa Kanamori, Takehiko Mori, Naoki Kobayashi, Tadakazu Kondo, Hirohisa Nakamae, Naoyuki Uchida, Masami Inoue, Takahiro Fukuda, Tatsuo Ichinohe, Yoshiko Atsuta, Yoshinobu Kanda
Natural killer (NK) cells assume graft-versus-leukemia alloreactivity after hematopoietic stem-cell transplantation (HSCT) through their inhibitory killer cell immunoglobulin-like receptors (KIRs). KIR2D family members recognize human leukocyte antigen (HLA)-C alleles with Asn80 (HLA-C1) or Lys80 (HLA-C2). The predominance of HLA-C1 over HLA-C2 and a frequent KIR2DL1 possession are characteristic of Japanese people. We compared clinical outcomes among homozygous HLA-C1 (HLA-C1/C1) patients and heterozygous HLA-C1/C2 patients who underwent HLA-matched HSCT for hematological malignancies by assessing the data of 10,638 patients from the Japanese national registry...
November 29, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29192343/a-view-on-the-importance-of-multi-attribute-method-for-measuring-purity-of-biopharmaceuticals-and-improving-overall-control-strategy
#15
Richard S Rogers, Michael Abernathy, Douglas D Richardson, Jason C Rouse, Justin B Sperry, Patrick Swann, Jette Wypych, Christopher Yu, Li Zang, Rohini Deshpande
Today, we are experiencing unprecedented growth and innovation within the pharmaceutical industry. Established protein therapeutic modalities, such as recombinant human proteins, monoclonal antibodies (mAbs), and fusion proteins, are being used to treat previously unmet medical needs. Novel therapies such as bispecific T cell engagers (BiTEs), chimeric antigen T cell receptors (CARTs), siRNA, and gene therapies are paving the path towards increasingly personalized medicine. This advancement of new indications and therapeutic modalities is paralleled by development of new analytical technologies and methods that provide enhanced information content in a more efficient manner...
November 30, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29189429/new-developments-in-immunotherapy-for-pediatric-solid-tumors
#16
Liora M Schultz, Robbie Majzner, Kara L Davis, Crystal Mackall
PURPOSE OF REVIEW: Building upon preclinical advances, we are uncovering immunotherapy strategies that are translating into improved outcomes in tumor subsets. Advanced pediatric solid tumors carry poor prognoses and resultant robust efforts to apply immunotherapy advances to pediatric solid tumors are in progress. Here, we discuss recent developments in the field using mAb and mAb-based therapies including checkpoint blockade and chimeric antigen receptors (CARs). RECENT FINDINGS: The pediatric solid tumor mAb experience targeting the diganglioside, GD2, for patients with neuroblastoma has been the most compelling to date...
November 20, 2017: Current Opinion in Pediatrics
https://www.readbyqxmd.com/read/29186979/the-need-for-immune-biomarkers-for-treatment-prognosis-and-response-in-genitourinary-malignancies
#17
Susan F Slovin
Immune biomarkers encompass a wide range of blood-borne and cell-associated molecules whose detection or expression may change in response to an immune therapy. These immune therapies encompass a range of platforms including autologous cellular products, in other words, dendritic cells, prime boost DNA vaccines, chimeric antigen receptor (CAR) T cells and checkpoint inhibitors. The response to checkpoint inhibitors by a particular cancer may not be necessarily associated with a change in a particular immune biomarker; other immune biomarkers are needed to assess their association with treatment response or a change in the biology that can impact on the immunologic milieu...
November 30, 2017: Biomarkers in Medicine
https://www.readbyqxmd.com/read/29185393/chimeric-switch-receptor-switching-for-improved-adoptive-t-cell-therapy-against-cancers
#18
Johan Ck Tay, Shijun Zha, Shu Wang
Adoptive T-lymphocyte transfer-based immunotherapy for cancers has seen huge leaps with both CARs and engineered TCRs. Despite this, issues relating to safety and efficacy persist. To address this, chimeric switch receptors have been created to reverse the outcomes of their original signaling pathways in order to confer immune cells with the ability to overcome the immunosuppressive tumor microenvironment and to allow them to have greater in vivo persistence. Activating switch receptors exploit the inhibitory molecules expressed by cancer cells to further stimulate the tumor antigen-specific T lymphocytes...
December 2017: Immunotherapy
https://www.readbyqxmd.com/read/29180536/high-affinity-gd2-specific-car-t-cells-induce-fatal-encephalitis-in-a-preclinical-neuroblastoma-model
#19
Sarah A Richman, Selene Nunez-Cruz, Babak Moghimi, Lucy Z Li, Zachary T Gershenson, Zissimos Mourelatos, David M Barrett, Stephan A Grupp, Michael C Milone
The GD2 ganglioside, which is abundant on the surface of neuroblastoma cells, is targeted by an FDA-approved therapeutic monoclonal antibody and is an attractive tumor-associated antigen for cellular immunotherapy. Chimeric antigen receptor (CAR)-modified T cells can have potent antitumor activity in B-cell malignancies, and trials to harness this cytolytic activity toward GD2 in neuroblastoma are underway. In an effort to enhance the antitumor activity of CAR T cells that target GD2, we generated variant CAR constructs predicted to improve the stability and the affinity of the GD2-binding, 14G2a-based, single-chain variable fragment (scFv) of the CAR, and compared their properties in vivo...
November 27, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29178361/outcome-of-patients-with-relapsed-refractory-acute-lymphoblastic-leukemia-after-blinatumomab-failure-no-change-in-the-level-of-cd19-expression
#20
Elias Jabbour, Johannes Düll, Musa Yilmaz, Joseph D Khoury, Farhad Ravandi, Nitin Jain, Hermann Einsele, Guillermo Garcia-Manero, Marina Konopleva, Nicholas J Short, Philip A Thompson, William Wierda, Naval Daver, Jorge Cortes, Susan O'Brien, Hagop Kantarjian, Max S Topp
Blinatumomab, a bi-specific T-cell engaging CD3-CD19 antibody construct, has shown significant activity in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL). Despite this improvement, most patients relapse. Here, we describe the outcome of 68 patients with R/R ALL after failure of blinatumomab therapy: 38 (56%) blinatumomab refractory; 30 (44%) relapsing after initial response. After a median follow-up of 49 months, 9 (13%) patients remained alive. The median overall survival after blinatumomab failure was 5...
November 27, 2017: American Journal of Hematology
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