Engineering Chimeric Antigen Receptors to Overcome the Immunosuppressive Solid Tumor Microenvironment PDF Download
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Author: Andrew J Hou
Publisher:
ISBN:
Category :
Languages : en
Pages : 118
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Book Description
Adoptive T-cell therapy is a cancer treatment strategy where T cells from a cancer patient are harvested, modified ex vivo to target tumor cells, and subsequently reinfused back into the patient's body. Although remarkably successful against blood-based B-cell malignancies, efficacy has been limited against solid tumors, in large part due to the immunosuppressive tumor microenvironment (TME). Among the many inhibitory factors in the TME, transforming growth factor-beta (TGF-[Beta]) plays a prominent role in suppressing anti-tumor immunity through both direct inhibition of T-cell cytotoxicity, as well as recruitment and polarization of immunosuppressive cell types such as myeloid-derived suppressor cells and regulatory T cells. We therefore hypothesized that T-cell function in the solid TME could be potentiated by pairing tumor-targeting CARs with TGF-[Beta] CARs that program T-cell activation, rather than inhibition, in the presence of TGF-[Beta]. Wefirst verified that TGF-[Beta] CAR expression is neither counterproductive to cytotoxic T-cell function, nor does it pose a significant risk of toxicity. Pairing TGF-[Beta] CARs with tumor-specific TCRs or CARs did not significantly enhance therapeutic outcomes of adoptive T-cell transfer in preclinical models of melanoma and prostate cancer, warranting further engineering efforts. In models of glioblastoma, however, single-chain bispecific CAR-T cells targeting TGF-[Beta] and tumor antigen were not only more resistant to tumor-mediated dysfunction, but also remodeled the immune-cell composition of the tumor microenvironment to potentiate anti-tumor immunity.
Author: Andrew J Hou
Publisher:
ISBN:
Category :
Languages : en
Pages : 118
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Book Description
Adoptive T-cell therapy is a cancer treatment strategy where T cells from a cancer patient are harvested, modified ex vivo to target tumor cells, and subsequently reinfused back into the patient's body. Although remarkably successful against blood-based B-cell malignancies, efficacy has been limited against solid tumors, in large part due to the immunosuppressive tumor microenvironment (TME). Among the many inhibitory factors in the TME, transforming growth factor-beta (TGF-[Beta]) plays a prominent role in suppressing anti-tumor immunity through both direct inhibition of T-cell cytotoxicity, as well as recruitment and polarization of immunosuppressive cell types such as myeloid-derived suppressor cells and regulatory T cells. We therefore hypothesized that T-cell function in the solid TME could be potentiated by pairing tumor-targeting CARs with TGF-[Beta] CARs that program T-cell activation, rather than inhibition, in the presence of TGF-[Beta]. Wefirst verified that TGF-[Beta] CAR expression is neither counterproductive to cytotoxic T-cell function, nor does it pose a significant risk of toxicity. Pairing TGF-[Beta] CARs with tumor-specific TCRs or CARs did not significantly enhance therapeutic outcomes of adoptive T-cell transfer in preclinical models of melanoma and prostate cancer, warranting further engineering efforts. In models of glioblastoma, however, single-chain bispecific CAR-T cells targeting TGF-[Beta] and tumor antigen were not only more resistant to tumor-mediated dysfunction, but also remodeled the immune-cell composition of the tumor microenvironment to potentiate anti-tumor immunity.
Author: Yushu Joy Xie
Publisher:
ISBN:
Category :
Languages : en
Pages : 154
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Book Description
Chimeric antigen receptor (CAR) T cells are a promising cancer therapeutic, as they can specifically redirect the cytotoxic function of a T cell to a chosen target of interest. CAR T cells have been successful in clinical trials against hematological cancers, but have experienced low efficacy against solid tumors for a number of reasons, including a paucity of tumor-specific antigens to target and a highly immunosuppressive solid tumor microenvironment. In chapter 2 of this thesis, we develop a strategy to target multiple solid tumor types through markers in their microenvironment. The use of single domain antibody (VHH)-based CAR T cells that recognize these markers circumvents the need for tumor-specific targets. Chapter 3 will describe methods to overcome the immunosuppressive microenvironment of solid tumors. Here, we have developed VHH-secreting CAR T cells that can modulate additional aspects of the tumor microenvironment, including the engagement of the innate immune system through secretion of a VHH against an inhibitor of phagocytosis. We show that this strategy of VHH-secretion by CAR T cells can lead to significant benefits in outcome. We also demonstrate that delivery of therapeutics by CAR T cells can improve the safety profile of the therapeutic. Chapter 4 of this thesis explores strategies to increase the targeting capacity of CAR T cells by building logic-gated CARs. Finally, chapter 5 will describe work in imaging CAR T cells specifically, longitudinally, and non-invasively through PET imaging. Our results demonstrate the flexibility of VHHs in CAR T cell engineering and the potential of VHH-based CAR T cells to target the tumor microenvironment, modulate the tumor microenvironment, and treat solid tumors.
Author: Ken Young
Publisher: Frontiers Media SA
ISBN: 2889767914
Category : Medical
Languages : en
Pages : 153
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Book Description
Author: Cheng Dong
Publisher: Springer
ISBN: 3319952943
Category : Medical
Languages : en
Pages : 376
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Book Description
This book covers multi-scale biomechanics for oncology, ranging from cells and tissues to whole organ. Topics covered include, but not limited to, biomaterials in mechano-oncology, non-invasive imaging techniques, mechanical models of cell migration, cancer cell mechanics, and platelet-based drug delivery for cancer applications. This is an ideal book for graduate students, biomedical engineers, and researchers in the field of mechanobiology and oncology. This book also: Describes how mechanical properties of cancer cells, the extracellular matrix, tumor microenvironment and immuno-editing, and fluid flow dynamics contribute to tumor progression and the metastatic process Provides the latest research on non-invasive imaging, including traction force microscopy and brillouin confocal microscopy Includes insight into NCIs’ role in supporting biomechanics in oncology research Details how biomaterials in mechano-oncology can be used as a means to tune materials to study cancer
Author: Chi-Wei Man
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Chimeric Antigen Receptor (CAR) T cell therapy is a revolutionary treatment option for cancer therapy, demonstrating widespread clinical success in treating hematological malignancies such as acute lymphoblastic leukemia and certain lymphomas. Despite its widespread success treating hematological malignancies, CAR T cells still struggle to treat solid tumors. One reason for this is the immunosuppressive tumor microenvironment. Expressed in certain tumors, Programmed Death-Ligand 1 (PD-L1) actively suppresses T cell activation and function. To both neutralize this immunoinhibitory effect and eliminate tumor cells, I used yeast display mediated directed evolution to engineer PDbody, derived from the monobody scaffold, to bind to PD-L1. I then employed PDbody as a SynNotch-gated CAR receptor to eliminate a triple-negative breast cancer model in vitro and slow tumor growth in vivo. CAR T cell therapy can also fail when tumors do not homogenously express the CAR target antigen. To combat this problem, I developed heat-inducible Cis-activated CAR (CisCAR) to allow CAR T cells to self-present their target antigen. I then used CisCAR to eliminate antigen-negative leukemic and breast cancer cells in vitro, demonstrating the universal applicability of this treatment strategy. Overall, this dissertation presents new methods that enhance CAR T cell therapy, enabling them to more effectively target a wider range of diseases.
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: 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: Anne Le
Publisher: Springer
ISBN: 331977736X
Category : Medical
Languages : en
Pages : 186
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Book Description
Genetic alterations in cancer, in addition to being the fundamental drivers of tumorigenesis, can give rise to a variety of metabolic adaptations that allow cancer cells to survive and proliferate in diverse tumor microenvironments. This metabolic flexibility is different from normal cellular metabolic processes and leads to heterogeneity in cancer metabolism within the same cancer type or even within the same tumor. In this book, we delve into the complexity and diversity of cancer metabolism, and highlight how understanding the heterogeneity of cancer metabolism is fundamental to the development of effective metabolism-based therapeutic strategies. Deciphering how cancer cells utilize various nutrient resources will enable clinicians and researchers to pair specific chemotherapeutic agents with patients who are most likely to respond with positive outcomes, allowing for more cost-effective and personalized cancer therapeutic strategies.
Author: Krassimir Metodiev
Publisher: BoD – Books on Demand
ISBN: 9535131052
Category : Medical
Languages : en
Pages : 416
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Book Description
This is another attempt of InTechOpen to continue the dissemination of international knowledge and experience in the field of immunology. The present book includes a number of modern concepts of specialists and experts in the field of immunotherapy, covering the major topics and analyzing the history, current stage, and future ideas of application of modern immunomodulation. It is always a benefit, but also a compliment, to gather a team of internationally distinguished authors and to motivate them to reveal their expertise for the benefit of medical science and health practice. On behalf of all readers, immunologists, immunogeneticists, biologists, oncologists, microbiologists, virologists, hematologists, chemotherapists, health-care experts, as well as students and medical specialists, also on my personal behalf, I would like to extend my gratitude and highest appreciation to InTechOpen for giving me the unique chance to be the editor of this exclusive book.
Author: Israel Vlodavsky
Publisher: Springer Nature
ISBN: 3030345211
Category : Medical
Languages : en
Pages : 871
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Book Description
Written by internationally recognized leaders in Heparanase biology, the book’s eight chapters offer an opportunity for scientists, clinicians and advanced students in cell biology, tumor biology and oncology to obtain a comprehensive understanding of Heparanase’s multifaceted activities in cancer, inflammation, diabetes and other diseases, as well as its related clinical applications. Proteases and their involvement in cancer progression have been well addressed and documented; however, the emerging premise presented within this book is that Heparanase is a master regulator of aggressive cancer phenotypes and crosstalk with the tumor microenvironment. This endoglycosidase contributes to tumor-mediated remodeling of the extracellular matrix and cell surfaces, augmenting the bioavailability of pro-tumorigenic and pro-inflammatory growth factors and cytokines that are bound to Heparan sulfate. Compelling evidence ties Heparanase with all steps of tumor progression including tumor initiation, growth, angiogenesis, metastasis, and chemoresistance, supporting the notion that Heparanase is an important contributor to the poor outcome of cancer patients and a validated target for therapy. Unlike Heparanase, heparanase-2, a close homolog of Heparanase, lacks enzymatic activity, inhibits Heparanase, and regulates selected genes that promote normal differentiation and tumor suppression. Written by internationally recognized leaders in Heparanase biology, this volume presents a comprehensive understanding of Heparanase’s multifaceted activities in cancer, inflammation, diabetes and other diseases, as well as its related clinical applications to scientists, clinicians and advanced students in cell biology, tumor biology and oncology.
