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https://www.readbyqxmd.com/read/30296188/tisagenlecleucel-t-for-the-treatment-of-acute-lymphocytic-leukemia
#1
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...
October 8, 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
#2
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
#3
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
#4
Karen T Mueller, Edward R Waldron, Stephan A Grupp, John E Levine, Theodore W Laetsch, Michael A Pulsipher, Michael W Boyer, Keith August, Jason Hamilton, Rakesh Awasthi, Andrew M Stein, Denise Sickert, Abhijit Chakraborty, Bruce L Levine, Carl H June, Lori Tomassian, Sweta Shah, Mimi Leung, Tetiana Taran, Patricia A Wood, Shannon L Maude
PURPOSE: 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). EXPERIMENTAL DESIGN: 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 2 studies in pediatric B-ALL (ELIANA; 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
#5
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...
June 2, 2018: Pediatric Neurology
https://www.readbyqxmd.com/read/30082906/management-guidelines-for-paediatric-patients-receiving-chimeric-antigen-receptor-t-cell-therapy
#6
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
#7
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
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/29746363/lower-extremity-fractures-in-hospitalized-pediatric-patients-following-road-traffic-accidents
#11
Shay Tenenbaum, Jason T Bariteau, Ofir Chechik, Adi Givon, Kobi Peleg, Ran Thein
Lower extremity fractures (LEFs) caused by road traffic accidents (RTAs) can result in significant morbidity and account for a substantial part of nonfatal injuries requiring hospitalization. This study investigated the epidemiology of RTA-associated LEFs in the pediatric population. Based on the National Trauma Registry, data of 28,924 RTA hospitalized pediatric patients were reviewed. Data were analyzed according to LEF mechanism of injury, age distribution, fracture types, associated injuries, surgical treatment, and their interrelations...
May 5, 2018: Pediatric Emergency Care
https://www.readbyqxmd.com/read/29731179/parents-adherence-to-pediatric-health-and-safety-guidelines-importance-of-patient-provider-relationships
#12
Lindsay N Fuzzell, A Scott LaJoie, Kyle T Smith, Sydney E Philpott, Katherine M Jones, Mary C Politi
OBJECTIVE: To examine 1) parent-provider communication about pediatric health/safety guidelines, 2) trust in child's provider, 3) comfort discussing guidelines, 4) agreement with guideline advice, 5) self-efficacy following guidelines, and their impact on guideline adherence. METHOD: 256 parents of children ages 0-6 completed an online survey about sunscreen use, newborn Vitamin K injections, influenza vaccination, routine vaccination, car seats, infant safe sleep, furniture anchoring, large trampoline use, and firearm safety...
September 2018: Patient Education and Counseling
https://www.readbyqxmd.com/read/29712574/durable-regression-of-medulloblastoma-after-regional-and-intravenous-delivery-of-anti-her2-chimeric-antigen-receptor-t-cells
#13
Anandani Nellan, Christopher Rota, Robbie Majzner, Cynthia M Lester-McCully, Andrea M Griesinger, Jean M Mulcahy Levy, Nicholas K Foreman, Katherine E Warren, Daniel W Lee
BACKGROUND: Standard-of-care therapies for treating pediatric medulloblastoma have long-term side effects, even in children who are cured. One emerging modality of cancer therapy that could be equally effective without such side effects would be chimeric antigen receptor (CAR) T cells. Knowing that human epidermal growth factor receptor 2 (HER2) is overexpressed in many medulloblastomas and has been used as a CAR T target before, we sought to evaluate the efficacy of more sophisticated anti-HER2 CAR T cells, as well as the feasibility and efficacy of different routes of delivering these cells, for the treatment of pediatric medulloblastoma...
April 30, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29662203/potent-antitumor-efficacy-of-anti-gd2-car-t-cells-in-h3-k27m-diffuse-midline-gliomas
#14
Christopher W Mount, Robbie G Majzner, Shree Sundaresh, Evan P Arnold, Meena Kadapakkam, Samuel Haile, Louai Labanieh, Esther Hulleman, Pamelyn J Woo, Skyler P Rietberg, Hannes Vogel, Michelle Monje, Crystal L Mackall
Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10 , and recent results suggest benefit in central nervous system malignancies11-13 . Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2...
May 2018: Nature Medicine
https://www.readbyqxmd.com/read/29622697/fda-approval-summary-tocilizumab-for-treatment-of-chimeric-antigen-receptor-t-cell-induced-severe-or-life-threatening-cytokine-release-syndrome
#15
Robert Q Le, Liang Li, Weishi Yuan, Stacy S Shord, Lei Nie, Bahru A Habtemariam, Donna Przepiorka, Ann T Farrell, Richard Pazdur
On August 30, 2017, the U.S. Food and Drug Administration approved Actemra (tocilizumab, Genentech, Inc., South San Francisco, CA) for the treatment of severe or life-threatening chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome (CRS) in adults and in pediatric patients 2 years of age and older. The approval was based on a retrospective analysis of data for patients who developed CRS after treatment with CTL019 and KTE-C19 on prospective clinical trials. Evaluable patients had been treated with intravenous tocilizumab 8 mg/kg (12 mg/kg for patients <30 kg) for severe or life-threatening CRS; only the first episode of CRS was included in the analysis...
August 2018: Oncologist
https://www.readbyqxmd.com/read/29605883/induction-of-a-central-memory-and-stem-cell-memory-phenotype-in-functionally-active-cd4-and-cd8-car-t-cells-produced-in-an-automated-good-manufacturing-practice-system-for-the-treatment-of-cd19-acute-lymphoblastic-leukemia
#16
Franziska Blaeschke, Dana Stenger, Theresa Kaeuferle, Semjon Willier, Ramin Lotfi, Andrew Didier Kaiser, Mario Assenmacher, Michaela Döring, Judith Feucht, Tobias Feuchtinger
Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4+ /CD8+ -separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB-based second generation CAR lentiviral vector...
July 2018: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29555644/biological-impact-of-%C3%AE-genes-%C3%AE-haplotypes-and-g6pd-activity-in-sickle-cell-anemia-at-baseline-and-with-hydroxyurea
#17
Françoise Bernaudin, Cécile Arnaud, Annie Kamdem, Isabelle Hau, Françoise Lelong, Ralph Epaud, Corinne Pondarré, Serge Pissard
Sickle cell anemia (SCA), albeit monogenic, has heterogeneous phenotypic expression, mainly related to the level of hemoglobin F (HbF). No large cohort studies have ever compared biological parameters in patients with major β-globin haplotypes; ie, Senegal (SEN), Benin (BEN), and Bantu/Central African Republic (CAR). The aim of this study was to evaluate the biological impact of α genes, β haplotypes, and glucose-6-phosphate dehydrogenase (G6PD) activity at baseline and with hydroxyurea (HU). Homozygous HbS patients from the Créteil pediatric cohort with available α-gene and β-haplotype data were included (n = 580; 301 females and 279 males) in this retrospective study...
March 27, 2018: Blood Advances
https://www.readbyqxmd.com/read/29501911/approved-car-t-cell-therapies-ice-bucket-challenges-on-glaring-safety-risks-and-long-term-impacts
#18
Ping-Pin Zheng, Johan M Kros, Jin Li
Two autologous chimeric antigen receptor (CAR) T cell therapies (Kymriah™ and Yescarta™) were recently approved by the FDA. Kymriah™ is for the treatment of pediatric patients and young adults with refractory or relapse (R/R) B cell precursor acute lymphoblastic leukemia and Yescarta™ is for the treatment of adult patients with R/R large B cell lymphoma. In common, both are CD19-specific CAR T cell therapies lysing CD19-positive targets. Their dramatic efficacy in the short term has been highlighted by many media reports...
June 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29499750/grading-of-cytokine-release-syndrome-associated-with-the-car-t-cell-therapy-tisagenlecleucel
#19
REVIEW
David Porter, Noelle Frey, Patricia A Wood, Yanqiu Weng, Stephan A Grupp
BACKGROUND: Anti-CD19 CAR T cell therapy has demonstrated high response rates in patients with relapsed or refractory (r/r) B cell malignancies but is associated with significant toxicity. Cytokine release syndrome (CRS) is the most significant complication associated with CAR T cell therapy, and it is critical to have a reproducible and easy method to grade CRS after CAR T cell infusions. DISCUSSION: The Common Terminology Criteria for Adverse Events scale is inadequate for grading CRS associated with cellular therapy...
March 2, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29442287/recent-developments-in-adolescent-and-young-adult-aya-acute-lymphoblastic-leukemia
#20
REVIEW
Victor M Orellana-Noia, Michael G Douvas
PURPOSE OF REVIEW: Adolescent and Young Adult (AYA) Oncology is a relatively new field encompassing research in the unique pathophysiology, clinical care, and psychosocial issues facing patients between the ages of 15 and 40 with cancer. About 100,000 of the approximately 1.5 million people diagnosed annually with cancer in the USA are in this age range. This chapter will review notable new developments in the care of adolescents and young adults with acute lymphoblastic leukemia (ALL) within the last 3 years...
April 2018: Current Hematologic Malignancy Reports
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