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CAR-T and pediatric

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https://read.qxmd.com/read/30873384/immunotherapeutic-targeting-of-gpc3-in-pediatric-solid-embryonal-tumors
#1
REVIEW
Michael V Ortiz, Stephen S Roberts, Julia Glade Bender, Neerav Shukla, Leonard H Wexler
Glypican 3 (GPC3) is a heparan sulfate proteoglycan and cell surface oncofetal protein which is highly expressed on a variety of pediatric solid embryonal tumors including the majority of hepatoblastomas, Wilms tumors, rhabdoid tumors, certain germ cell tumor subtypes, and a minority of rhabdomyosarcomas. Via both its core protein and heparan sulfate side chains, GPC3 activates the canonical Wnt/β-catenin pathway, which is frequently overexpressed in these malignancies. Loss of function mutations in GPC3 lead to Simpson-Golabi-Behmel Syndrome, an X-linked overgrowth condition with a predisposition to GPC3-expressing cancers including hepatoblastoma and Wilms tumor...
2019: Frontiers in Oncology
https://read.qxmd.com/read/30863720/next-generation-car-t-cells-for-the-immunotherapy-of-high-grade-glioma
#2
REVIEW
Christopher T Petersen, Giedre Krenciute
High grade gliomas (HGG) comprise a heterogeneous group of brain malignancies with dismal prognosis. Current standard-of-care includes radiation, chemotherapy, and surgical resection when possible. Despite advances in each of these treatment modalities, survival rates for pediatric and adult HGG patients has remained largely unchanged over the course of several years. This is in stark contrast to the significant survival increases seen recently for a variety of hematological and other solid malignancies. The introduction and widespread use of immunotherapies have contributed significantly to these survival increases, and as such these therapies have been explored for use in the treatment of HGG...
2019: Frontiers in Oncology
https://read.qxmd.com/read/30860496/cd19-car-t-cell-product-and-disease-attributes-predict-leukemia-remission-durability
#3
Olivia C Finney, Hannah M Brakke, Stephanie Rawlings-Rhea, Roxana Hicks, Danielle Doolittle, Marisa Lopez, Robert B Futrell, Rimas J Orentas, Daniel Li, Rebecca A Gardner, Michael C Jensen
BACKGROUND: Chimeric antigen receptor (CAR) T cells can induce remission in highly refractory leukemia and lymphoma subjects, yet the parameters for achieving sustained relapse-free survival are not fully delineated. METHODS: We analyzed 43 pediatric and young adult subjects participating in a Phase I trial of defined composition CD19CAR T cells (NCT02028455). CAR T cell phenotype, function and expansion, as well as starting material T cell repertoire, were analyzed in relation to therapeutic outcome (defined as achieving complete remission within 63 days) and duration of leukemia free survival and B cell aplasia...
March 12, 2019: Journal of Clinical Investigation
https://read.qxmd.com/read/30784101/car-t-cells-for-acute-lymphoblastic-leukemia
#4
Noelle V Frey
Chimeric Antigen Receptor (CAR) modified T cells targeted to CD19 have resulted in unprecedented remission rates for adult and pediatric patients with relapsed and refractory B cell acute lymphoblastic leukemia (ALL). With regulatory approval for tisagenlecleucel and many other agents under active investigation, the use of CAR T cells for ALL continues to expand. While some remissions from anti-CD19 CAR T cells are durable without a consolidative allogeneic stem cell transplantation, CD19 positive and negative relapses remain a significant concern fueling investigations into the biology of CAR T cell persistence and the development of CARTs that target more than one antigen...
February 19, 2019: American Journal of Hematology
https://read.qxmd.com/read/30764841/clinical-trials-of-dual-target-car-t-cells-donor-derived-car-t-cells-and-universal-car-t-cells-for-acute-lymphoid-leukemia
#5
REVIEW
Juanjuan Zhao, Yongping Song, Delong Liu
The current treatment for pediatric acute lymphoblastic leukemia (ALL) is highly successful with high cure rate. However, the treatment of adult ALL remains a challenge, particularly for refractory and/or relapsed (R/R) ALL. The advent of new targeted agents, blinatumomab, inotuzumab ozogamycin, and chimeric antigen receptor (CAR) T cells, are changing the treatment paradigm for ALL. Tisagenlecleucel (kymriah, Novartis) is an autologous CD19-targeted CAR T cell product approved for treatment of R/R B cell ALL and lymphoma...
February 14, 2019: Journal of Hematology & Oncology
https://read.qxmd.com/read/30716352/immunotherapy-in-pediatric-b-cell-acute-lymphoblastic-leukemia
#6
REVIEW
Kirk D Wyatt, Richard J Bram
Advances in multi-agent chemotherapy and supportive care have dramatically improved survival of children with B-cell acute lymphoblastic leukemia (B-ALL); however, patients with relapsed and refractory disease continue to represent a therapeutic challenge. Hematopoietic stem cell transplant was the first immunotherapeutic approach to be used in the treatment of patients with relapsed or refractory disease. However, novel therapies such as bispecific antibodies that engage T-cells and chimeric antigen receptor T-cells (CAR-T) therapy have emerged as novel FDA-approved options that have the potential to become the new standard of care for these difficult-to-treat leukemias...
February 1, 2019: Human Immunology
https://read.qxmd.com/read/30686354/traitement-par-car-t-des-leuc%C3%A3-mies-aigu%C3%A3-s-de-l-adulte
#7
REVIEW
Ilhem Rahal, Aurélie Cabannes-Hamy, Nicolas Boissel
The prognosis for acute lymphoblastic leukemia (ALL) in adults remains poor in refractory or relapsed (R/R) situations. Among the immunotherapy strategies that have recently been developed, CAR-T cells (chimeric antigen receptor modified T-cells) represent a major technological and therapeutic advance in the management of adult and pediatric patients with such resistant diseases. The first CAR-T trials targeting the ubiquitous B-cell antigen CD19 showed very encouraging results with complete remission rates of approximately 80%...
December 2018: Bulletin du Cancer
https://read.qxmd.com/read/30670684/the-journey-to-car-t-cell-therapy-the-pediatric-and-young-adult-experience-with-relapsed-or-refractory-b-all
#8
REVIEW
George Hucks, Susan R Rheingold
Outcomes of pediatric and young adult patients diagnosed with acute lymphoblastic leukemia (ALL) have improved significantly in the past few decades. Treatment advances have provided 5-year survival rates ranging from 78 to 91% depending on the age at diagnosis. However, approximately 2-3% of patients will present with refractory disease that is unresponsive to chemotherapy, and 10-15% of patients will relapse. Outcomes post-relapse show significantly reduced 5-year survival rates that continue to decrease with each subsequent relapse...
January 22, 2019: Blood Cancer Journal
https://read.qxmd.com/read/30666506/industry-s-giant-leap-into-cellular-therapy-catalyzing-chimeric-antigen-receptor-t-cell-car-t-immunotherapy
#9
REVIEW
Stacie Ittershagen, Solveig Ericson, Lamis Eldjerou, Ali Shojaee, Eric Bleickardt, Manisha Patel, Tetiana Taran, Oezlem Anak, Charlene Hall, Mimi Leung, Deborah Roccoberton, Florence Salmon, Miriam Fuchs, Vadim Romanov, David Lebwohl
PURPOSE OF REVIEW: We describe the significant technological leap from bench to bedside that was achieved through a strong academic-industry collaboration between dedicated clinicians and researchers at the University of Pennsylvania, the Children's Hospital of Philadelphia, and Novartis to commercialize the chimeric antigen receptor T cell (CAR-T) therapy tisagenlecleucel (CTL019; Kymriah®; Novartis Pharma AG, Basel, Switzerland). RECENT FINDINGS: Tisagenlecleucel was the first CAR-T therapy and the first gene therapy to receive US Food and Drug Administration approval in 2017, with an initial indication for pediatric and young adult patients with relapsed or refractory (r/r) acute lymphoblastic leukemia, followed by approval in May 2018 for a second indication in adult patients with r/r diffuse large B cell lymphoma...
January 21, 2019: Current Hematologic Malignancy Reports
https://read.qxmd.com/read/30661749/-management-of-cytokine-release-syndrome-in-adult-and-pediatric-patients-undergoing-car-t-cell-therapy-for-hematological-malignancies-recommendation-of-the-french-society-of-bone-marrow-and-cellular-therapy-sfgm-tc
#10
REVIEW
Ibrahim Yakoub-Agha, Anne-Sophie Moreau, Imran Ahmad, Cécile Borel, Nawal Hadhoum, Stavroula Masouridi-Levrat, Jérôme Naudin, Emmanuelle Nicolas-Virelizier, Marie Ouachée-Chardin, Lara Platon, Asmaa Quessar, Gabrielle Roth-Guepin, Davis Beauvais, André Baruchel, Jérôme Cornillon
The cytokine release syndrome (CRS) is the most common complication after adoptive immunotherapies such as chimeric antigen receptor T cells (CAR-T). The incidence varies from 30 to 100% depending on the CAR-T construct, cell doses and the underlying disease. Severe cases may involve 10 to 30% of patients. The triggering event is the activation of the CAR-T, after meeting with their target. The T cell activation leads to the release of effector cytokines, such as IFNγ, TNFα and IL2, that are responsible for the activating of monocyte/macrophage system, resulting in the production of pro-inflammatory cytokines, (including IL6, IFN-γ, IL10, MCP1) and associated with a significant elevation of CRP and ferritin...
January 17, 2019: Bulletin du Cancer
https://read.qxmd.com/read/30655315/car-t-cells-targeting-b7-h3-a-pan-cancer-antigen-demonstrate-potent-preclinical-activity-against-pediatric-solid-tumors-and-brain-tumors
#11
Robbie G Majzner, Johanna L Theruvath, Anandani Nellan, Sabine Heitzeneder, Yongzhi Cui, Christopher W Mount, Skyler P Rietberg, Miles H Linde, Peng Xu, Christopher Rota, Elena Sotillo, Louai Labanieh, Daniel W Lee, Rimas J Orentas, Dimiter S Dimitrov, Zhongyu Zhu, Brad St Croix, Alberto Delaidelli, Alla Sekunova, Ezio Bonvini, Siddhartha S Mitra, Martha M Quezado, Ravindra Majeti, Michelle Monje, Poul Hb Sorensen, John M Maris, Crystal L Mackall
PURPOSE: Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T cell therapy of pediatric solid tumors, including those arising in the central nervous system...
January 17, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://read.qxmd.com/read/30630850/naive-t-cell-deficits-at-diagnosis-and-after-chemotherapy-impair-cell-therapy-potential-in-pediatric-cancers
#12
Rajat K Das, Lauren Vernau, Stephan A Grupp, David M Barrett
Translational data on chimeric antigen receptor (CAR) T cell trials indicates the presence of naive T cells in the pre-manufacture product is important to clinical response and persistence. In anticipation of developing CAR trials for other tumors, we investigated the T cell distribution from children with solid tumors and lymphomas at diagnosis and after every cycle of chemotherapy. We found that patients with T cells enriched for naive and stem central memory cells expanded well in vitro, but the majority of tumor types showed chemotherapy related depletion of early lineage cells with a corresponding decline in successful ex vivo stimulation response...
January 10, 2019: Cancer Discovery
https://read.qxmd.com/read/30629377/-recent-advances-and-future-directions-in-car-t-cell-therapy-in-pediatric-oncology
#13
Francesco Ceppi, Raffaele Renella, Manuel Diezi, Marc Ansari, Michel A Duchosal, Caroline Arber, Lana Kandalaft, George Coukos, Maja Beck-Popovic
Fighting leukemia using the immune system (antibodies, lymphocytes) is an old idea, which has already been fulfilled in allogeneic bone marrow transplantation. Indeed, the effectiveness of the transplant depends on the action of the donor lymphocytes. To limit the adverse effects on bystander organs (graft-versus-host disease), autologous T cells can be engineered to express synthetic chimeric antigen receptors (CARs) with artificially redirected antigen specificity. Autologous T cells engineered to express a CAR targeting CD19 have shown unprecedented efficacy in clinical trials for relapsed/refractory B-cell leukemias and lymphomas...
January 9, 2019: Revue Médicale Suisse
https://read.qxmd.com/read/30612698/-some-important-breakthroughs-in-oncology-and-hematology-in-2018-a-selection-by-the-editorial-board-of-bulletin-du-cancer
#14
REVIEW
Jacques-Olivier Bay, Thierry André, Christophe Caux, Serge Evrard, Antony Gonçalves, Gilles L'Allemain, Nicolas Magné, Daniel Orbach, Nicolas Penel, Manuel Rodrigues, Juliette Thariat, Antoine Thiery-Vuillemin, Marie Wislez
The editorial board of Bulletin du Cancer presents some hot topics published or presented in major oncology meetings in 2018. This selection is related to pediatric oncology and to solid and hemato-malignancies in adults, with immunotherapy approaches (checkpoints or CAR-T) as one of the major breakthroughs. Putative impacts on daily practices are discussed, in order to detail what will really change our practice.
January 3, 2019: Bulletin du Cancer
https://read.qxmd.com/read/30596389/a-spheroid-killing-assay-by-car-t-cells
#15
Pierre Dillard, Hakan Köksal, Else-Marit Inderberg, Sebastien Wälchli
Immunotherapy has become a field of growing interest in the fight against cancer otherwise untreatable. Among all immunotherapeutic methods, chimeric antigen receptor (CAR) redirected T cells obtained the most spectacular results, in particular with pediatric B-acute lymphoblastic leukemia (B-ALL). Classical validation methods of CAR T cells rely on the use of specificity and functionality assays of the CAR T cells against target cells in suspension and in xenograft models. Unfortunately, observations made in vitro are often decoupled from results obtained in vivo and a lot of effort and animals could be spared by adding another step: the use of 3D culture...
December 12, 2018: Journal of Visualized Experiments: JoVE
https://read.qxmd.com/read/30595201/nouvelles-perspectives-dans-l%C3%A2-immunoth%C3%A3-rapie-des-cancers-p%C3%A3-diatriques
#16
Claudia Pasqualini, Fanny Rialland, Dominique Valteau-Couanet, Jean Michon, Véronique Minard-Colin
New therapeutic paradigms are needed to improve the survival of children and adolescents with high-risk malignancies, and to reduce the sequelae associated with treatment. Immunotherapies, targeting tumor cells and/or the immune system to enhance existing anti-tumor immunity or induce novel anti-tumor immune responses, are becoming increasingly successful in adult oncology. Based on the results obtained with anti-ganglioside2 antibodies in neuroblastoma, rituximab in mature B malignancies, immune checkpoint inhibitors in lymphoma and especially in Hodgkin lymphoma, blinatumomab and CAR-T CD19 cells for B-cell acute lymphoblastic leukemia, immunotherapy has demonstrated irrefutable benefits in pediatric patients...
December 2018: Bulletin du Cancer
https://read.qxmd.com/read/30560413/mechanisms-and-management-of-chimeric-antigen-receptor-t-cell-therapy-related-toxicities
#17
REVIEW
Bhagirathbhai R Dholaria, Christina A Bachmeier, Frederick Locke
Chimeric antigen receptor T-cell (CAR-T) therapy has proven to be a very effective cancer immunotherapy. Axicabtagene ciloleucel and tisagenlecleucel are the first-in-class anti-CD19 CAR-T currently available for relapsed/refractory adult large B-cell lymphoma. Tisagenlecleucel is also available for pediatric and young adult (up to age 25 years) patients with relapsed/refractory B-acute lymphoblastic leukemia. Cytokine release syndrome (CRS) and CAR-T-associated encephalopathy syndrome (neurotoxicity) are the most common adverse effects associated with CAR-T therapy...
December 17, 2018: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://read.qxmd.com/read/30559740/car-t-cell-therapy-of-non-hematopoietic-malignancies-detours-on-the-road-to-clinical-success
#18
REVIEW
Kristen B Long, Regina M Young, Alina C Boesteanu, Megan M Davis, J Joseph Melenhorst, Simon F Lacey, David A DeGaramo, Bruce L Levine, Joseph A Fraietta
Chimeric antigen receptor (CAR)-engineered T cells represent a breakthrough in personalized medicine. In this strategy, a patient's own T lymphocytes are genetically reprogrammed to encode a synthetic receptor that binds a tumor antigen, allowing T cells to recognize and kill antigen-expressing cancer cells. As a result of complete and durable responses in individuals who are refractory to standard of care therapy, CAR T cells directed against the CD19 protein have been granted United States Food and Drug Administration (FDA) approval as a therapy for treatment of pediatric and young adult acute lymphoblastic leukemia and diffuse large B cell lymphoma...
2018: Frontiers in Immunology
https://read.qxmd.com/read/30551196/cost-effectiveness-of-chimeric-antigen-receptor-t-cell-therapy-in-pediatric-relapsed-refractory-b-cell-acute-lymphoblastic-leukemia
#19
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://read.qxmd.com/read/30528964/recent-advances-in-car-t-cell-toxicity-mechanisms-manifestations-and-management
#20
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
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