Genome Engineering to Expand Applications of Human T-cell Immunotherapy PDF Download
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Author: Alexandra E. Grier
Publisher:
ISBN:
Category :
Languages : en
Pages : 102
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Book Description
Adoptive T-cell therapy, particularly chimeric antigen receptor (CAR) therapy, is a revolutionary and quickly-evolving means of treating cancer patients who can no longer be helped by standard therapies. In multiple clinical trials, including our own at Seattle Children’s Hospital, CD19 CAR therapy for B-cell leukemia and lymphoma has achieved a complete remission rate of >90%. Unfortunately, in its present form, CAR therapy has had limited success against solid tumors. It is also not currently an option for patients who lack sufficient numbers of their own T-cells due to their disease or prior treatments. Thus, genome engineering strategies to overcome these limitations could be of great benefit to patients. We chose a two-pronged approach to achieve this goal: knock-out of the endogenous TCR and multiplex knock-out of the T-cell inhibitory checkpoints PD-1, Tim3, Lag3, and TIGIT. Knocking out these inhibitory checkpoint proteins specifically in the CAR T-cells will maintain the synergistic effects recently seen in combination monoclonal antibody therapy without the serious, sometimes fatal, immune-mediated side effects seen with systemic antibody therapy. To this end, we first developed a linear mRNA expression vector with a long, encoded poly(A) tail to allow transient delivery of nucleases such as TALENs or CRISPR to primary human cells in a consistent, clinically applicable, and scalable fashion. We then used IVT mRNA made from this vector to deliver a TALEN pair targeting the TCR locus to CD19 CAR T-cells, and demonstrated that removal of the endogenous TCR does not hinder CAR T-cell function in vitro or in vivo in a murine xenograft tumor model. Knockout of the endogenous TCR will facilitate production of an allogeneic CAR T-cell product to be used as a bridge to HSCT in patients who cannot receive autologous CAR therapy. Removal of the endogenous TCR will also add a measure of safety when creating CAR T-cells lacking inhibitory checkpoint proteins by preventing GvHD while retaining anti-tumor effects. These technologies and methods may allow a wider variety of patients to benefit from the recent advances in CAR T-cell therapy.
Author: Alexandra E. Grier
Publisher:
ISBN:
Category :
Languages : en
Pages : 102
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Book Description
Adoptive T-cell therapy, particularly chimeric antigen receptor (CAR) therapy, is a revolutionary and quickly-evolving means of treating cancer patients who can no longer be helped by standard therapies. In multiple clinical trials, including our own at Seattle Children’s Hospital, CD19 CAR therapy for B-cell leukemia and lymphoma has achieved a complete remission rate of >90%. Unfortunately, in its present form, CAR therapy has had limited success against solid tumors. It is also not currently an option for patients who lack sufficient numbers of their own T-cells due to their disease or prior treatments. Thus, genome engineering strategies to overcome these limitations could be of great benefit to patients. We chose a two-pronged approach to achieve this goal: knock-out of the endogenous TCR and multiplex knock-out of the T-cell inhibitory checkpoints PD-1, Tim3, Lag3, and TIGIT. Knocking out these inhibitory checkpoint proteins specifically in the CAR T-cells will maintain the synergistic effects recently seen in combination monoclonal antibody therapy without the serious, sometimes fatal, immune-mediated side effects seen with systemic antibody therapy. To this end, we first developed a linear mRNA expression vector with a long, encoded poly(A) tail to allow transient delivery of nucleases such as TALENs or CRISPR to primary human cells in a consistent, clinically applicable, and scalable fashion. We then used IVT mRNA made from this vector to deliver a TALEN pair targeting the TCR locus to CD19 CAR T-cells, and demonstrated that removal of the endogenous TCR does not hinder CAR T-cell function in vitro or in vivo in a murine xenograft tumor model. Knockout of the endogenous TCR will facilitate production of an allogeneic CAR T-cell product to be used as a bridge to HSCT in patients who cannot receive autologous CAR therapy. Removal of the endogenous TCR will also add a measure of safety when creating CAR T-cells lacking inhibitory checkpoint proteins by preventing GvHD while retaining anti-tumor effects. These technologies and methods may allow a wider variety of patients to benefit from the recent advances in CAR T-cell therapy.
Author: Victor Tieu
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Decades of research in synthetic biology and immunology have endowed us with the blueprints for a new therapeutic modality: the engineered immune cell. Specifically, Chimeric Antigen Receptor (CAR) T cell therapy has proven to be a breakthrough in the treatment of relapsed or refractory hematologic cancers. Furthermore, recent advances in synthetic biology, such as the discovery and development of CRISPR/Cas9 technologies that facilitate precision genome engineering and control of molecular-cellular processes, offer innovative solutions to major challenges that limit the use of CAR T cells in solid tumors and other cancers. However, current CRISPR/Cas9 gene editing tools are limited in their safety, efficacy, and scope. To address these challenges, we present MEGA (Multiplexed Effector Guide Arrays), a versatile and multi-functional platform for programmable and scalable regulation of the T cell transcriptome using the RNA-guided, RNA-targeting activity of CRISPR/Cas13d. MEGA enables quantitative, reversible, and massively-multiplexed gene knockdown in primary human T cells without targeting or cutting genomic DNA. Applying MEGA to a model of CAR T cell dysfunction, we demonstrate robust multiplexed suppression of canonical exhaustion-associated genes, perform a first-in-class combinatorial CRISPR/Cas13d screen to uncover paired regulators of T cell proliferation, and utilize these findings to enhance the anti-tumor activity of dysfunctional CAR T cells. We also establish a novel method to link the expression of multiple endogenous genes to the dosage of an FDA-approved drug, which we use to regulate CAR activation strength in a receptor-independent manner. Lastly, we generate MEGA CAR T cells with a diverse range of gene-set perturbations -- with up to 10 genes targeted at once -- and functionally disrupt an entire metabolic pathway to counteract adenosine-driven T cell immunosuppression. Compared to conventional genome editing, MEGA provides a unique synthetic immunology toolkit with applications in cancer immunotherapy, next-generation CAR T cell therapies, and beyond.
Author: Klaus Schindhelm
Publisher: Academic Press
ISBN:
Category : Health & Fitness
Languages : en
Pages : 392
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Book Description
R.E. Nordon and K. Schindhelm, Introduction. -- L. Robb, A.G. Elefanty, and C.G. Begley, Transcriptional Control of Hematopoieses. -- R. Starr and N.A. Nicola, Cell Signaling by Hemopoietic Growth Factor Receptors. -- P.J. Simmons, D.N. Haylock, and J.-P. Lévesque, Influence of Cytokines and Adhesion Molecules on Hematopoietic Stem Cell Development. -- P.A. Rowlings, Allogeneic Hematopoietic Stem Cell Transplantation. -- U. Hahn and L.B. To, Autologous Stem Cell Transplantation. -- M.R. Vowels, Cord Blood Stem Cell Transplantation. -- S.R. Riddell, E.H. Warren, D. Lewinsohn, C. Yee, and P.D. Greenberg, Reconstitution of Immunity by Adoptive Immunotherapy with T Cells. -- L.Q. Sun, M. Miller, and G. Symonds, Exogenous Gene Transfer into Lymphoid and Hematopoietic Progenitor Cells. -- C. Dowding, T. Leemhuis, A. Jakubowski, and C. Reading, Process Development for Ex Vivo Cell Therapy. -- R.E. Nordon and K. Schindhelm, Cell Separation. -- P.W. Zandstra, C.J. Eaves, and J.M. Piret, Environ ...
Author: The Royal Society
Publisher: National Academies Press
ISBN: 0309671132
Category : Medical
Languages : en
Pages : 239
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Book Description
Heritable human genome editing - making changes to the genetic material of eggs, sperm, or any cells that lead to their development, including the cells of early embryos, and establishing a pregnancy - raises not only scientific and medical considerations but also a host of ethical, moral, and societal issues. Human embryos whose genomes have been edited should not be used to create a pregnancy until it is established that precise genomic changes can be made reliably and without introducing undesired changes - criteria that have not yet been met, says Heritable Human Genome Editing. From an international commission of the U.S. National Academy of Medicine, U.S. National Academy of Sciences, and the U.K.'s Royal Society, the report considers potential benefits, harms, and uncertainties associated with genome editing technologies and defines a translational pathway from rigorous preclinical research to initial clinical uses, should a country decide to permit such uses. The report specifies stringent preclinical and clinical requirements for establishing safety and efficacy, and for undertaking long-term monitoring of outcomes. Extensive national and international dialogue is needed before any country decides whether to permit clinical use of this technology, according to the report, which identifies essential elements of national and international scientific governance and oversight.
Author: National Academies of Sciences, Engineering, and Medicine
Publisher: National Academies Press
ISBN: 0309452880
Category : Medical
Languages : en
Pages : 329
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Book Description
Genome editing is a powerful new tool for making precise alterations to an organism's genetic material. Recent scientific advances have made genome editing more efficient, precise, and flexible than ever before. These advances have spurred an explosion of interest from around the globe in the possible ways in which genome editing can improve human health. The speed at which these technologies are being developed and applied has led many policymakers and stakeholders to express concern about whether appropriate systems are in place to govern these technologies and how and when the public should be engaged in these decisions. Human Genome Editing considers important questions about the human application of genome editing including: balancing potential benefits with unintended risks, governing the use of genome editing, incorporating societal values into clinical applications and policy decisions, and respecting the inevitable differences across nations and cultures that will shape how and whether to use these new technologies. This report proposes criteria for heritable germline editing, provides conclusions on the crucial need for public education and engagement, and presents 7 general principles for the governance of human genome editing.
Author: L.E. Samelson
Publisher:
ISBN: 9783318018981
Category : Medical
Languages : en
Pages : 0
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Book Description
Author: John Masters
Publisher: Springer Science & Business Media
ISBN: 0306468727
Category : Medical
Languages : en
Pages : 295
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Book Description
Continuous cell lines derived from human cancers are the most widely used resource in laboratory-based cancer research. The first 3 volumes of this series on Human Cell Culture are devoted to these cancer cell lines. The chapters in these first 3 volumes have a common aim. Their purpose is to address 3 questions of fundamental importance to the relevance of human cancer cell lines as model systems of each type of cancer: 1. Do the cell lines available accurately represent the clinical presentation? 2. Do the cell lines accurately represent the histopathology of the original tumors? 3. Do the cell lines accurately represent the molecular genetics of this type of cancer? The cancer cell lines available are derived, in most cases, from the more aggressive and advanced cancers. There are few cell lines derived from low grade organ-confined cancers. This gap can be filled with conditionally immortalized human cancer cell lines. We do not know why the success rate for establishing cell lines is so low for some types of cancer and so high for others. The histopathology of the tumor of origin and the extent to which the derived cell line retains the differentiated features of that tumor are critical. The concept that a single cell line derived from a tumor at a particular site is representative of tumors at that site is naïve and misleading.
Author: Gerald J. Prud'homme
Publisher: Springer
ISBN: 9780306479915
Category : Medical
Languages : en
Pages : 149
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Book Description
Autoimmune diseases are diverse and responsible for considerable morbidity. Their etiology remains largely unknown, and current therapy with anti-inflammatory drugs is prone to adverse effects, and rarely curative. New therapies with anti-cytokine antibodies or receptors are promising, but require frequent administration of expensive protein drugs. Gene Therapy of Autoimmune Diseases comprehensively reviews research in gene therapy for autoimmune diseases with viral or non-viral vectors. Gene therapy offers the possibility of long-term, continuous delivery of a wide variety of immunosuppressive, anti-inflammatory, or tolerance-inducing agents. Moreover, highly specific genetically modified cells can be produced. This book discusses the most promising avenues in this exciting new field.
Author: Nicolaus Kröger
Publisher: Springer Nature
ISBN: 3030943534
Category : Medical
Languages : en
Pages : 221
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Book Description
This first open access European CAR-T Handbook, co-promoted by the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA), covers several aspects of CAR-T cell treatments, including the underlying biology, indications, management of side-effects, access and manufacturing issues. This book, written by leading experts in the field to enhance readers’ knowledge and practice skills, provides an unparalleled overview of the CAR-T cell technology and its application in clinical care, to enhance readers’ knowledge and practice skills.
Author: Rodolphe Barrangou
Publisher: Springer Science & Business Media
ISBN: 364234657X
Category : Science
Languages : en
Pages : 300
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Book Description
CRISPR/Cas is a recently described defense system that protects bacteria and archaea against invasion by mobile genetic elements such as viruses and plasmids. A wide spectrum of distinct CRISPR/Cas systems has been identified in at least half of the available prokaryotic genomes. On-going structural and functional analyses have resulted in a far greater insight into the functions and possible applications of these systems, although many secrets remain to be discovered. In this book, experts summarize the state of the art in this exciting field.
