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CAR-T and pediatric

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https://www.readbyqxmd.com/read/30551196/cost-effectiveness-of-chimeric-antigen-receptor-t-cell-therapy-in-pediatric-relapsed-refractory-b-cell-acute-lymphoblastic-leukemia
#1
Reith R Sarkar, Nicholas J Gloude, Deborah Schiff, James D Murphy
Background: Chimeric antigen receptor T-cell (CAR-T) therapy is a promising new class of cancer therapy but has a high up-front cost. We evaluated the cost-effectiveness of CAR-T therapy among pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Methods: We built a microsimulation model for pediatric patients with relapsed/refractory B-ALL receiving either CAR-T therapy or standard of care. Outcomes included costs, quality of life (health utility), complications, and survival...
December 14, 2018: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/30528964/recent-advances-in-car-t-cell-toxicity-mechanisms-manifestations-and-management
#2
REVIEW
Jennifer N Brudno, James N Kochenderfer
Chimeric antigen receptor (CAR) T-cell therapy is an effective new treatment for hematologic malignancies. Two CAR T-cell products are now approved for clinical use by the U.S. FDA: tisagenlecleucel for pediatric acute lymphoblastic leukemia (ALL) and adult diffuse large B-cell lymphoma subtypes (DLBCL), and axicabtagene ciloleucel for DLBCL. CAR T-cell therapies are being developed for multiple myeloma, and clear evidence of clinical activity has been generated. A barrier to widespread use of CAR T-cell therapy is toxicity, primarily cytokine release syndrome (CRS) and neurologic toxicity...
November 14, 2018: Blood Reviews
https://www.readbyqxmd.com/read/30524966/a-unique-human-immunoglobulin-heavy-chain-variable-domain-only-cd33-car-for-the-treatment-of-acute-myeloid-leukemia
#3
Dina Schneider, Ying Xiong, Peirong Hu, Darong Wu, Weizao Chen, Tianlei Ying, Zhongyu Zhu, Dimiter S Dimitrov, Boro Dropulic, Rimas J Orentas
Acute myeloid leukemia (AML) remains a challenging pediatric and adult disease. Given the elevated expression of the CD33 antigen on leukemic blasts, therapeutic approaches to AML now feature the approved antibody drug conjugate (Mylotarg, GO) and investigational CART cell approaches incorporating CD33-binding domains derived from humanized scFvs. We designed a functional chimeric antigen receptor utilizing a human targeting sequence, derived from a heavy chain variable domain, termed CAR33VH. Lentiviral-based expression vectors which encoded CAR constructs incorporating the novel binding domain (CAR33VH), or the My96 scFv control binder (My96CAR) in frame with a CD8 hinge and transmembrane domain, a 4-1BB costimulatory domain and a CD3 zeta activation domain, were transduced into primary human CD4+ and CD8+ T cells, and CAR expression was confirmed by flow cytometry...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/30504287/are-car-t-cells-better-than-antibody-or-hct-therapy-in-b-all
#4
REVIEW
Michael A Pulsipher
Multicenter trials in children and young adults using second-generation CD19-targeted chimeric antigen receptor (CAR) T cells have shown dramatic levels of remission in patients with multiply relapsed/refractory disease (80% to ≥90%). Early results in adult trials have also shown significant responses, and strategies aimed at mitigating toxicities associated with the therapy have improved tolerability. Therefore, if available, CAR T-cell therapy deserves consideration for salvage of children and adults with B-lineage acute lymphoblastic leukemia (B-ALL) who are multiply relapsed, refractory, or relapsed after a previous allogeneic transplantation...
November 30, 2018: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/30489654/combined-heparin-acid-citrate-dextrose-solution-a-anticoagulation-in-the-optia-continuous-mononuclear-cell-protocol-for-pediatric-lymphocyte-apheresis
#5
Robert A DeSimone, Gary D Myers, Erin M Guest, Patricia A Shi
Collecting a sufficient number of T-cells is a critical first step in the production of chimeric antigen receptor (CAR)-T cells. Herein, we report a successful implementation of anticoagulation with combined heparin and acid citrate dextrose solution A (ACD-A) for the continuous mononuclear cell (CMNC) protocol on the Spectra Optia in a 20-month-old, 7.5 kg patient with refractory acute lymphoblastic leukemia for manufacture of tisagenlecleucel, a CAR-T cell therapy. Combined heparin/ACD-A was used following clotting issues when ACD-A was used alone during initial CMNC collections...
November 29, 2018: Journal of Clinical Apheresis
https://www.readbyqxmd.com/read/30483473/carbohydrate-targets-for-car-t-cells-in-solid-childhood-cancers
#6
REVIEW
Claudia Rossig, Sareetha Kailayangiri, Silke Jamitzky, Bianca Altvater
Application of the CAR targeting strategy in solid tumors is challenged by the need for adequate target antigens. As a consequence of their tissue origin, embryonal cancers can aberrantly express membrane-anchored gangliosides. These are carbohydrate molecules consisting of a glycosphingolipid linked to sialic acids residues. The best-known example is the abundant expression of ganglioside GD2 on the cell surface of neuroblastomas which derive from GD2 -positive neuroectoderm. Gangliosides are involved in various cellular functions, including signal transduction, cell proliferation, differentiation, adhesion and cell death...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/30459530/chimeric-antigen-receptors-unleashing-a-new-age-of-anti-cancer-therapy
#7
REVIEW
Yan Leyfman
Background: Chimeric antigen receptors (CARs) represent a novel facet of modern day synthetic biology that exemplifies personalized medicine at work through their ability to harness and redirect a patient's immune system to fight cancer. Body: By combining the target-specificity of antibodies to the effector capabilities of T cells, CARs have yielded high remission rates for many late staged and relapsed/refractory (r/r) hematological malignancies, including acute lymphoblastic leukemias (ALL) and Non-Hodgkin's lymphomas...
2018: Cancer Cell International
https://www.readbyqxmd.com/read/30450661/pediatricians-proficiency-in-the-care-of-the-dysphonic-child
#8
Carly S Schiff, Karen B Zur, Lisa M Biggs, Jia Guo, Michael J Pitman
OBJECTIVES/HYPOTHESIS: Pediatricians are the first physicians to see a dysphonic child (DC), yet there are limited data on their proficiency in caring for them. The objective of this study was to understand how pediatricians' experience and their comfort in recognizing/diagnosing voice disorders affects their referral patterns and use of basic treatment options. STUDY DESIGN: Survey study. METHODS: A 13-question survey was sent to pediatricians in the Children's Hospital of Philadelphia's primary care network; 45/216 were returned...
November 19, 2018: Laryngoscope
https://www.readbyqxmd.com/read/30406956/advances-in-chimeric-antigen-receptor-car-t-cell-therapies-for-solid-tumors
#9
Trevor R Baybutt, John C Flickinger, Ellen M Caparosa, Adam E Snook
In 2017, the United States Food and Drug Administration (FDA) approved the first two novel cellular immunotherapies using synthetic, engineered receptors known as chimeric antigen receptors (CAR), tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), expressed by patient-derived T cells for the treatment of hematological malignancies expressing the B-cell surface antigen CD19 in both pediatric and adult patients. This approval marked a major milestone in the use of antigen-directed 'living drugs' for the treatment of relapsed or refractory blood cancers, and with these two approvals, there is increased impetus to expand not only the target antigens but also the tumor types that can be targeted...
November 8, 2018: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/30346363/utilization-of-a-clinical-decision-support-tool-to-reduce-child-tobacco-smoke-exposure-in-the-urgent-care-setting
#10
Esther Melinda Mahabee-Gittens, Ashley L Merianos, Judith W Dexheimer, Gabe T Meyers, Lara Stone, Meredith Tabangin, Jane C Khoury, Judith S Gordon
BACKGROUND: Clinical decision support systems (CDSS) may facilitate caregiver tobacco screening and counseling by pediatric urgent care (UC) nurses. OBJECTIVE: This study aimed to assess the feasibility of a CDSS to address caregivers' tobacco use and child tobacco smoke exposure (TSE). METHODS: We conducted a 3-month prospective study on caregivers screened using a CDSS. Nurses used the CDSS to advise, assess, and assist caregivers to quit...
October 19, 2018: Pediatric Emergency Care
https://www.readbyqxmd.com/read/30296188/tisagenlecleucel-t-for-the-treatment-of-acute-lymphocytic-leukemia
#11
Xavier Thomas, Etienne Paubelle
Cellular immunotherapy with autologous or allogeneic T cells, genetically engineered to express chimeric antigen receptors (CARs) or T-cell receptors, in order to redirect their cytotoxic specificity toward malignant cells, is emerging as a promising new treatment modality. The most advanced approach in clinical development is the use of anti-CD19 CAR T-cells for the treatment of CD19+ B-cell malignancies, including acute lymphocytic leukemia (ALL). Areas covered: Recently, the Food and Drug Administration (FDA) approved the first anti-CD19 CAR T-cell product, tisagenlecleucel, for the treatment of pediatric and young adult patients with relapsed/refractory ALL...
November 2018: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/30233192/the-potential-of-car-t-therapy-for-relapsed-or-refractory-pediatric-and-young-adult-b-cell-all
#12
REVIEW
Matthew H Forsberg, Amritava Das, Krishanu Saha, Christian M Capitini
Recent advancements in immunooncology have resulted in the generation of novel therapies such as chimeric antigen receptor (CAR) T cells, which have revolutionized the treatment of pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia. The journey of tisagenlecleucel (formerly CTL019) from early preclinical success to the US Food and Drug Administration approval is summarized in this review. Strategies that are currently being investigated to improve the efficacy and safety profile of CAR T-cells are also explored, as well as the factors contributing to the present state of patient access to CAR T therapy...
2018: Therapeutics and Clinical Risk Management
https://www.readbyqxmd.com/read/30231350/the-landscape-of-car-t-cells-beyond-acute-lymphoblastic-leukemia-for-pediatric-solid-tumors
#13
REVIEW
Christopher DeRenzo, Giedre Krenciute, Stephen Gottschalk
Adoptive cell therapy with genetically modified T cells holds the promise to improve outcomes for children with recurrent/refractory solid tumors and has the potential to reduce treatment complications for all patients. Although T cells that express chimeric antigen receptors (CARs) specific for CD19 have had remarkable success for B-cell-derived malignancies, which has led to their approval by the U.S. Food and Drug Administration, CAR T cells have been less effective for solid tumors and brain tumors. Lack of efficacy is most likely multifactorial, but heterogeneous antigen expression; limited migration of T cells to tumor sites; and the immunosuppressive, hostile tumor microenvironment have emerged as major roadblocks that must be addressed...
May 23, 2018: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/30190371/clinical-pharmacology-of-tisagenlecleucel-in-b-cell-acute-lymphoblastic-leukemia
#14
Karen Thudium Mueller, Edward Waldron, Stephan A Grupp, John E Levine, Theodore W Laetsch, Michael A Pulsipher, Michael W Boyer, Keith J August, Jason Hamilton, Rakesh Awasthi, Andrew M Stein, Denise Sickert, Abhijit Chakraborty, Bruce L Levine, Carl H June, Lori Tomassian, Sweta S Shah, Mimi Leung, Tetiana Taran, Patricia A Wood, Shannon L Maude
Background: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Methods: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN)...
September 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/30126755/neurological-complications-of-the-treatment-of-pediatric-neoplastic-disorders
#15
REVIEW
Lisa R Sun, Stacy Cooper
Neurological complications resulting from childhood cancer treatments are common. Treatment for childhood neoplastic disorders is often multimodal and may include procedures, cranial irradiation, chemotherapy, transplant, and immunotherapy, each of which carries distinct neurological risks. Procedures, such as lumbar punctures, are commonly used in this population for diagnostic purposes as well as intrathecal medication administration. Surgery is associated with an array of potential neurological complications, with posterior fossa syndrome being a common cause of morbidity in pediatric brain tumor patients after neurosurgical resection...
August 2018: Pediatric Neurology
https://www.readbyqxmd.com/read/30082906/management-guidelines-for-paediatric-patients-receiving-chimeric-antigen-receptor-t-cell-therapy
#16
REVIEW
Kris M Mahadeo, Sajad J Khazal, Hisham Abdel-Azim, Julie C Fitzgerald, Agne Taraseviciute, Catherine M Bollard, Priti Tewari, Christine Duncan, Chani Traube, David McCall, Marie E Steiner, Ira M Cheifetz, Leslie E Lehmann, Rodrigo Mejia, John M Slopis, Rajinder Bajwa, Partow Kebriaei, Paul L Martin, Jerelyn Moffet, Jennifer McArthur, Demetrios Petropoulos, Joan O'Hanlon Curry, Sarah Featherston, Jessica Foglesong, Basirat Shoberu, Alison Gulbis, Maria E Mireles, Lisa Hafemeister, Cathy Nguyen, Neena Kapoor, Katayoun Rezvani, Sattva S Neelapu, Elizabeth J Shpall
In 2017, an autologous chimeric antigen receptor (CAR) T cell therapy indicated for children and young adults with relapsed and/or refractory CD19+ acute lymphoblastic leukaemia became the first gene therapy to be approved in the USA. This innovative form of cellular immunotherapy has been associated with remarkable response rates but is also associated with unique and often severe toxicities, which can lead to rapid cardiorespiratory and/or neurological deterioration. Multidisciplinary medical vigilance and the requisite health-care infrastructure are imperative to ensuring optimal patient outcomes, especially as these therapies transition from research protocols to standard care...
August 6, 2018: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/29925499/nonviral-rna-chimeric-antigen-receptor-modified-t-cells-in-patients-with-hodgkin-lymphoma
#17
Jakub Svoboda, Susan R Rheingold, Saar I Gill, Stephan A Grupp, Simon F Lacey, Irina Kulikovskaya, Megan M Suhoski, J Joseph Melenhorst, Brandon Loudon, Anthony R Mato, Sunita Dwivedy Nasta, Daniel J Landsburg, Matthew R Youngman, Bruce L Levine, David L Porter, Carl H June, Stephen J Schuster
Chimeric antigen receptor (CAR)-modified T cells are being investigated in many settings, including classical Hodgkin lymphoma (cHL). The unique biology of cHL, characterized by scant Hodgkin and Reed-Sternberg (HRS) cells within an immunosuppressive tumor microenvironment (TME), may pose challenges for cellular therapies directly targeting antigens expressed on HRS cells. We hypothesized that eradicating CD19+ B cells within the TME and the putative circulating CD19+ HRS clonotypic cells using anti-CD19-directed CAR-modified T cells (CART19) may indirectly affect HRS cells, which do not express CD19...
September 6, 2018: Blood
https://www.readbyqxmd.com/read/29797659/myeloid-lineage-switch-following-chimeric-antigen-receptor-t-cell-therapy-in-a-patient-with-tcf3-znf384-fusion-positive-b-lymphoblastic-leukemia
#18
Matthew J Oberley, Paul S Gaynon, Deepa Bhojwani, Michael A Pulsipher, Rebecca A Gardner, Matthew C Hiemenz, Jianling Ji, Jennifer Han, Maurice R G O'Gorman, Alan S Wayne, Gordana Raca
A pediatric patient diagnosed initially with B-lymphoblastic leukemia (B-ALL) relapsed with lineage switch to acute myeloid leukemia (AML) after chimeric antigen receptor T-cell (CAR-T) therapy and hematopoietic stem cell transplant. A TCF3-ZNF384 fusion was identified at diagnosis, persisted through B-ALL relapse, and was also present in the AML relapse cell population. ZNF384-rearrangements define a molecular subtype of B-ALL characterized by a pro-B-cell immunophenotype; furthermore, ZNF384-rearrangements are prevalent in mixed-phenotype acute leukemias...
September 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29772353/cardiac-profile-of-chimeric-antigen-receptor-t-cell-therapy-in-children-a-single-institution-experience
#19
Danielle S Burstein, Shannon Maude, Stephen Grupp, Heather Griffis, Joseph Rossano, Kimberly Lin
Immunotherapy with chimeric antigen receptor (CAR)-modified T cells targeting CD19 for pediatric acute lymphoblastic leukemia (ALL) has demonstrated significant efficacy. The principle toxicity is cytokine release syndrome with resultant hypotension. However, the spectrum of cardiovascular effects associated with CAR T cell therapy has not been systematically evaluated. We reviewed all patients who received CD19-directed CAR T cells at the Children's Hospital of Philadelphia between April 2012 and September 2016...
August 2018: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29764159/emerging-role-of-immunotherapy-for-childhood-cancers
#20
REVIEW
Rupert Handgretinger, Patrick Schlegel
Recent developments in cell and gene therapy have a great impact on the new therapeutic approaches in pediatric cancers. Monoclonal antibodies for neuroblastoma and bispecific antibodies for leukemia have induced significant clinical responses for otherwise chemorefractory patients. Moreover, cellular therapeutic approaches including chimeric antigen receptor (CAR) T-cells as well as natural killer (NK) cells have the potential to cure patients with so far incurable malignancies and are the basis for future new therapies for pediatric cancer...
April 2018: Chinese Clinical Oncology
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