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Hematology/oncology Clinics of North America

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https://www.readbyqxmd.com/read/28895857/gene-therapy
#1
EDITORIAL
Daniel E Bauer, Donald B Kohn
No abstract text is available yet for this article.
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28895856/gene-modified-t-cell-therapies-for-hematological-malignancies
#2
REVIEW
Ulrike Abramowski-Mock, Juliette M Delhove, Waseem Qasim
This article focuses on clinical applications of T cells transduced to express recombinant T cell receptor and chimeric antigen receptor constructs directed toward hematological malignancies, and considers newer strategies incorporating gene-editing technologies to address GvHD and host-mediated rejection. Recent data from clinical trials are reviewed, and an overview is provided of current and emerging manufacturing processes; consideration is also given to new developments in the pipeline.
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28895855/hematopoietic-stem-cell-approaches-to-cancer
#3
REVIEW
Jennifer E Adair, Sara P Kubek, Hans-Peter Kiem
Hematopoietic stem cells (HSCs) are unique in their ability to self-renew and generate all blood lineages for the entire life. HSC modification affects red blood cells, platelets, lymphocytes, and myeloid cells. Chemotherapy can result in myelosuppression, limiting effective chemotherapy administration. For diseases like glioblastoma, high expression of methlylguanine methyltransferase can inactivate alkylating agent chemotherapy. Here we discuss how HSCs can be modified to overcome this resistance, permitting sensitization of tumors to chemotherapy while simultaneously protecting the hematopoietic system...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28895854/gene-therapy-approaches-to-human-immunodeficiency-virus-and-other-infectious-diseases
#4
REVIEW
Geoffrey L Rogers, Paula M Cannon
Advances in gene therapy technologies, particularly in gene editing, are suggesting new avenues for the treatment of human immunodeficiency virus and other infectious diseases. This article outlines recent developments in antiviral gene therapies, including those based on the disruption of entry receptors or that target viral genomes using targeted nucleases, such as the CRISPR/Cas9 system. In addition, new ways to express circulating antiviral factors, such as antibodies, and approaches to harness and engineer the immune system to provide an antiviral effect that is not naturally achieved are described...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28895853/hematopoietic-gene-therapies-for-metabolic-and-neurologic-diseases
#5
REVIEW
Alessandra Biffi
Increasingly, patients affected by metabolic diseases affecting the central nervous system and neuroinflammatory disorders receive hematopoietic cell transplantation (HCT) in the attempt to slow the course of their disease, delay or attenuate symptoms, and improve pathologic findings. The possible replacement of brain-resident myeloid cells by the transplanted cell progeny contributes to clinical benefit. Genetic engineering of the cells to be transplanted (hematopoietic stem cell) may endow the brain myeloid progeny of these cells with enhanced or novel functions, contributing to therapeutic effects...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28895852/gene-therapy-for-hemophilia
#6
REVIEW
Amit C Nathwani, Andrew M Davidoff, Edward G D Tuddenham
The best currently available treatments for hemophilia A and B (factor VIII or factor IX deficiency, respectively) require frequent intravenous infusion of highly expensive proteins that have short half-lives. Factor levels follow a saw-tooth pattern that is seldom in the normal range and falls so low that breakthrough bleeding occurs. Most hemophiliacs worldwide do not have access to even this level of care. In stark contrast, gene therapy holds out the hope of a cure by inducing continuous endogenous expression of factor VIII or factor IX following transfer of a functional gene to replace the hemophilic patient's own defective gene...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28895851/gene-therapy-approaches-to-hemoglobinopathies
#7
REVIEW
Giuliana Ferrari, Marina Cavazzana, Fulvio Mavilio
Gene therapy for hemoglobinopathies is currently based on transplantation of autologous hematopoietic stem cells genetically modified with a lentiviral vector expressing a globin gene under the control of globin transcriptional regulatory elements. Preclinical and early clinical studies showed the safety and potential efficacy of this therapeutic approach as well as the hurdles still limiting its general application. In addition, for both beta-thalassemia and sickle cell disease, an altered bone marrow microenvironment reduces the efficiency of stem cell harvesting as well as engraftment...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28895850/gene-therapy-approaches-to-immunodeficiency
#8
REVIEW
Sujal Ghosh, H Bobby Gaspar
Transfer of gene-corrected autologous hematopoietic stem cells in patients with primary immunodeficiencies has emerged as a new therapeutic approach. Patients with various conditions lacking a suitable donor have been treated with retroviral vectors and a gene-addition strategy. Initial promising results were shadowed by the occurrence of malignancies in some of these patients. Current trials, developed in the last decade, use safer viral vectors to overcome the risk of genotoxicity and have led to improved clinical outcomes...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28895849/opening-marrow-niches-in-patients-undergoing-autologous-hematopoietic-stem-cell-gene-therapy
#9
REVIEW
Morton J Cowan, Christopher C Dvorak, Janel Long-Boyle
Successful gene therapy for genetic disorders requires marrow niches to be opened to varying degrees to engraft gene-corrected hematopoietic stem cells (HSC). For example, in severe combined immunodeficiency, relatively limited chimerism is necessary for both T- and B-cell immune reconstitution, whereas for inborn errors of metabolism maximal donor chimerism is the goal. Currently, alkylating chemotherapy is used for this purpose. Significant pharmacokinetic variability exists in drug clearance in children less than 12 years old...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28895848/gene-editing-regulatory-and-translation-to-clinic
#10
REVIEW
Dale Ando, Kathleen Meyer
The clinical application and regulatory strategy of genome editing for ex vivo cell therapy is derived from the intersection of two fields of study: viral vector gene therapy trials; and clinical trials with ex vivo purification and engraftment of CD34(+) hematopoietic stem cells, T cells, and tumor cell vaccines. This article covers the regulatory and translational preclinical activities needed for a genome editing clinical trial modifying hematopoietic stem cells and the genesis of this current strategy based on previous clinical trials using genome-edited T cells...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28895847/therapeutic-gene-editing-safety-and-specificity
#11
REVIEW
Christopher T Lux, Andrew M Scharenberg
Therapeutic gene editing is significant for medical advancement. Safety is intricately linked to the specificity of the editing tools used to cut at precise genomic targets. Improvements can be achieved by thoughtful design of nucleases and repair templates, analysis of off-target editing, and careful utilization of viral vectors. Advancements in DNA repair mechanisms and development of new generations of tools improve targeting of specific sequences while minimizing risks. It is important to plot a safe course for future clinical trials...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28895846/in%C3%A2-vivo-hematopoietic-stem-cell-transduction
#12
REVIEW
Maximilian Richter, Daniel Stone, Carol Miao, Olivier Humbert, Hans-Peter Kiem, Thalia Papayannopoulou, André Lieber
Current protocols for hematopoietic stem cell (HSC) gene therapy, involving the transplantation of ex vivo lentivirus vector-transduced HSCs into myeloablated recipients, are complex and not without risk for the patient. In vivo HSC gene therapy can be achieved by the direct modification of HSCs in the bone marrow after intraosseous injection of gene delivery vectors. A recently developed approach involves the mobilization of HSCs from the bone marrow into peripheral the blood circulation, intravenous vector injection, and re-engraftment of genetically modified HSCs in the bone marrow...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28895845/nonintegrating-gene-therapy-vectors
#13
REVIEW
Takis Athanasopoulos, Mustafa M Munye, Rafael J Yáñez-Muñoz
Gene delivery vectors that do not rely on host cell genome integration offer several advantages for gene transfer, chiefly the avoidance of insertional mutagenesis and position effect variegation. However, unless engineered for replication and segregation, nonintegrating vectors will dilute progressively in proliferating cells, and are not exempt of epigenetic effects. This article provides an overview of the main nonintegrating viral (adenoviral, adeno-associated viral, integration-deficient retro-lentiviral, poxviral), and nonviral (plasmid vectors, artificial chromosomes) vectors used for preclinical and clinical cell and gene therapy applications...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28895844/integrating-vectors-for-gene-therapy-and-clonal-tracking-of-engineered-hematopoiesis
#14
REVIEW
Luca Biasco, Michael Rothe, Juliane W Schott, Axel Schambach
Gene therapy using autologous or allogeneic cells offers promising possibilities to treat inherited and acquired diseases, ideally leading to a long-lasting therapeutic correction. This article summarizes efforts that use integrating vectors derived from retroviruses and transposons, and briefly explains integrating vector biology and integration site analysis and recent successful application of this technology in clinical trials. Moreover, outlined is how these vectors can be used for cancer gene discovery and clonal tracking of benign and malignant hematopoiesis to gain insights into the dynamics of hematopoiesis...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28895843/historical-perspective-on-the-current-renaissance-for-hematopoietic-stem-cell-gene-therapy
#15
REVIEW
Donald B Kohn
Gene therapy using hematopoietic stem cells (HSC) has developed over the past 3 decades, with progressive improvements in the efficacy and safety. Autologous transplantation of HSC modified with murine gammaretroviral vectors first showed clinical benefits for patients with several primary immune deficiencies, but some of these patients suffered complications from vector-related genotoxicity. Lentiviral vectors have been used recently for gene addition to HSC and have yielded clinical benefits for primary immune deficiencies, metabolic diseases, and hemoglobinopathies, without vector-related complications...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28673398/kinase-inhibitors-in-the-treatment-of-myeloid-malignancies
#16
EDITORIAL
Ann Mullally
No abstract text is available yet for this article.
August 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28673397/identification-and-targeting-of-kinase-alterations-in-histiocytic-neoplasms
#17
REVIEW
Neval Ozkaya, Ahmet Dogan, Omar Abdel-Wahab
Histiocytic disorders represent clonal disorders of cells believed to be derived from the monocyte, macrophage, and/or dendritic cell lineage presenting with a range of manifestations. Although their nature as clonal versus inflammatory nonclonal conditions have long been debated, recent studies identified numerous somatic mutations that activate mitogen-activated protein kinase signaling in clinically and histologically diverse forms of histiocytosis. Clinical trials and case series have revealed that targeting aberrant kinase signaling using BRAF and/or MEK inhibitors may be effective...
August 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28673396/kinase-inhibitor-screening-in-myeloid-malignancies
#18
REVIEW
Jeffrey W Tyner
Kinase pathways are primary effectors of many targeted therapy approaches for cancer. Kinase pathways can be dysregulated by mechanisms far more diverse than chromosomal rearrangements or point mutations, which drove the initial application of kinase inhibitors to cancer. Functional screening with kinase inhibitors is one tool by which we can understand the diversity of target kinases and candidate drugs for patients before fully understanding the mechanistic rationale for kinase pathway dysregulation. By combining functional screening with genomic data, it is also possible to accelerate understanding of these mechanistic underpinnings...
August 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28673395/mechanisms-of-resistance-to-flt3-inhibitors-and-the-role-of-the-bone-marrow-microenvironment
#19
REVIEW
Gabriel Ghiaur, Mark Levis
The presence of FLT3 mutations in acute myeloid leukemia (AML) carries a particularly poor prognosis, making the development of FLT3 inhibitors an imperative goal. The last decade has seen an abundance of clinical trials using these drugs alone or in combination with chemotherapy. This culminated with the recent approval by the US Food and Drug Administration of Midostaurin for the treatment of FLT3-mutated AML. Initial success has been followed by the emergence of clinical resistance. Although novel FLT3 inhibitors are being developed, studies into mechanisms of resistance raise hope of new strategies to prevent emergence of resistance and eliminate minimal residual disease...
August 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28673394/the-development-of-flt3-inhibitors-in-acute-myeloid-leukemia
#20
REVIEW
Jacqueline S Garcia, Richard M Stone
FLT3 mutations, generally associated with a poor prognosis, are found in approximately one-third of patients with acute myeloid leukemia (AML) and represent an attractive therapeutic target. FLT3 inhibitors undergoing clinical evaluation include first-generation relatively non-specific small molecules and second-generation compounds with higher potency and selectivity against mutant FLT3. Recently presented results from a prospective randomized clinical trial will likely lead to a change in the standard of care for younger patients with FLT3-mutated AML: addition of the multi-targeted FLT3 inhibitor midostaurin to standard induction and consolidation chemotherapy...
August 2017: Hematology/oncology Clinics of North America
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