Download or read book Approaches to Improve the Proliferation and Activity of Natural Killer Cells for Adoptive Cell Therapy written by Evelyn Ojo and published by . This book was released on 2019 with total page 218 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer is the second-leading cause of death in the United States and worldwide leading to 8.8 million deaths in 2015. Despite major advancements in science and health, patients at advanced stages of particular cancer types experience significant mortality. Cancer patients often relapse following treatment with conventional therapeutic modalities such as chemotherapy and radiation therapy. Conventional treatment approaches do not successfully address the heterogeneity present in most solid tumors, result in severe off-target effects resulting in severe side effects, and fail to kill dormant cancer cells. Immunotherapy is the use of immune cells as tools to combat diseases. Natural killer (NK) cells are lymphocytes that lyse tumor cells and virally-infected cells through diverse mechanisms including release of cytotoxic granules. NK cell therapy has shown much promise in preclinical studies however it fails to demonstrate efficacy in various cancer populations. This body of work tackles two crucial barriers to NK cell therapy in patients with solid tumors. NK cell numbers in the tumor has been correlated with good prognosis in cancer patients. Obtaining clinically efficacious numbers of NK cells is limited by the relatively small proportion of NK cells in peripheral blood. We, therefore, designed and engineered a novel IL-21-based NK cell expansion platform consisting of OCI-AML3 cells transduced with membrane-bound IL-21 (NKF cells). We demonstrated that NKF cells are effective at expanding NK cells. The NK cells expanded using NKF cells were able to lyse a wide array of tumor types and demonstrated a favorable metabolic signature as compared to non-expanded NK cells. Additionally, NKF-expanded NK cells significantly reduced the tumor burden in sarcoma cell-infected mice. Cancer cells have developed mechanisms to evade anti-tumor activities of NK cells, dampening the efficacy of NK cell-mediated lysis of cancer cells. Transforming growth factor-ß (TGF-ß) is an immunosuppressive cytokine abundantly secreted by cancer cells to modify the cancer landscape to support the growth and development of the tumor. We demonstrated that inhibition of TGF-ß using the clinical grade TGF-ß inhibitor, galunisertib, resulted in rescue of NK cell cytokine secretion and cytotoxic function. In conclusion, this work has evaluated the NKF expansion system and demonstrated its ability to robustly expand NK cells. NKF-expanded NK cells have increased glycolytic and oxidative phosphorylation rates and continue to expand beyond 5 weeks of expansion. Feeder cell-expanded NK cells demonstrate superior cytotoxic function following inhibition of TGF-ß signaling. Infusion of NKF-expanded NK cells coupled with TGF-ß inhibition has the potential to result in decreased tumor burden in cancer patients.
Download or read book Current Perspectives Challenges and Advances in Cell Based Therapies written by Prashant Trikha and published by Frontiers Media SA. This book was released on 2020-03-24 with total page 192 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Targeting CD155 Interactions to Enhance Natural Killer Cell Therapy for Osteosarcoma written by Monica Moonkyung Cho and published by . This book was released on 2023 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Osteosarcoma (OS) is the most common primary bone tumor in pediatric patients, and patients that present with metastatic disease have a poor prognosis and no curative treatment options. Natural killer (NK) cells are a promising avenue for antitumor response. Using NK cells from a donor, or allogeneic NK cells, can enhance antitumor activity by recognizing the patient's tumor as non-self, preventing inhibition caused by recognition of self MHC Class I. Administration of allogeneic NK cells in the context of allogeneic hematopoietic stem cell transplant (alloHSCT) promotes NK cell proliferation and reduces the risk of graft rejection by matching the alloHSCT and NK cell donor sources. Further, NK cell activity can be augmented by taking advantage of immune checkpoints, such as CD155. CD155 is overexpressed on various tumor types, including osteosarcoma, and is associated with poor prognosis. Blocking CD155 can interfere with dominant inhibitory interactions to allow NK cell to become activated in CD155-expressing tumors such as OS. We proposed combining allogeneic NK cells with CD155 checkpoint blockade to enhance NK cell anti-OS activity. Allogeneic NK cells exhibited superior cytotoxicity against CD155-expressing OS compared to syngeneic NK cells, and this activity was further enhanced by CD155 blockade. We observed that CD155 blockade increased allogeneic NK cell degranulation and interferon gamma production when stimulated by CD155-expressing OS, and these functions were abrogated when DNAM-1 blockade was added. We treated mice with pulmonary OS disease with allogeneic bone marrow transplant (BMT), followed by treatment with allogeneic EAE NK cell infusion and CD155 blockade. We found that CD155 blockade increased survival and decreased OS disease burden compared to mice that received isotype control. We performed RNA microarray analysis using lung tissue from OS bearing mice treated with alloBMT, alloNK and CD155 axis blockade. In mice treated with CD155 blockade, genes related to NK cell cytotoxicity were upregulated. These results demonstrate efficacy of allogeneic NK cells combined with CD155 blockade to mount an antitumor response against CD155-expressing OS. Translation of combination adoptive NK cell and CD155 axis modulatory treatment approaches offer promising new therapies for pediatric patients with relapsed and refractory solid tumors.
Download or read book Novel Immunotherapeutic Approaches to the Treatment of Cancer written by Paul D. Rennert and published by Springer. This book was released on 2016-05-30 with total page 285 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer care is undergoing a radical transformation as novel technologies are directed toward new treatments and personalized medicine. The most dramatic advances in the treatment of cancer have come from therapeutics that augment the immune response to tumors. The immune checkpoint inhibitors are the best-known and most highly advanced examples of Immune Therapeutics targeting tumor cells and include approved antibody drugs directed at the cell surface proteins CTLA4 and PD-1. These are now considered foundational treatments for several solid tumor indications, and that list of indications is growing quickly. More broadly, antibodies have become workhorse molecules across the entire immunotherapy landscape. Antibodies to novel targets modulate the activity of diverse immune cell regulatory proteins. Engineered antibodies can induce tumor cell death or expose tumor cells to poisonous toxins (ADCC and ADC, respectively). Bi-specific antibodies can engage multiple tumor targets simultaneously, or can redirect lymphocytes to attack tumor cells. The antigen-binding domains within antibodies can be spliced onto cell stimulatory domains and transduced into T cells or NK cells, creating remarkable tumor-specific cellular therapeutics (CAR-T, CAR-NK). Beyond antibody-based therapies there are highly diverse and differentiated technology tool kits being applied to immunotherapy. Small molecule drugs are being developed to attack the tumor microenvironment, novel tumor vaccine approaches are showing great promise, patient lymphocytes are being isolated, expanded and reintroduced to patients, gene-editing techniques are becoming widely deployed, and a vast number of new tumor targets, and mutated tumor proteins (neoantigens), are being discovered. The past decade has seen unprecedented success in the treatment of diverse cancers. The authors of this volume have been asked to not only review progress to date, but importantly, to look ahead, and anticipate the evolution of cancer treatment across diverse Immune Therapeutic approaches. Our hypothesis is that the advances we are seeing across the immunotherapy landscape will further evolve and synergize, leading us finally to outright cures for many cancers.
Download or read book NK Cell Based Cancer Immunotherapy written by and published by . This book was released on 2016 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Natural killer (NK) cells are innate lymphoid cells that have a significant role in regulating the defenses against cancer development and certain viral infections. They are equipped with an array of activating and inhibitory receptors that stimulate or diminish NK cell activity, respectively. Inhibitory receptors include, among others, the MHC class I ligands killer cell immunoglobulin-like receptors (KIR) in humans, and members of the Ly49 family of receptors in mice, and CD94/NKG2A. Activating receptors include cytokine and chemokine receptors, and those that interact with ligands expressed on target cells, such as the natural cytotoxicity receptors or NCRs (NKp30, NKp44 and NKp46), NKG2D, CD244 and DNAM-1. In addition, NK cells express Fc?RIIIA or CD16, the receptor that exerts antibody-dependent cell mediated cytotoxicity (ADCC). NK cells also express the death ligands FasL and TRAIL. The killing or sparing of target cells depends on the integration of distinct signals that originate from NK cell receptors. NK cells spare healthy cells that express normal levels of MHC class I molecules and low amounts of stress-induced self-molecules, whereas they kill target cells that down-regulate MHC class I molecules and/or up-regulate stress-induced self-molecules. The latter are common signatures of virus-infected cells and tumors. All the accumulated knowledge on NK cell biology, along with many clinical observations, is driving multiple efforts to improve the arsenal of NK cell-based therapeutic tools in the fight against malignant diseases. Indeed, NK cell-based immunotherapy is becoming a promising approach for the treatment of many cancers. It is well known that NK cells have a significant role in the anti-tumor effect of therapeutic antibodies that use ADCC as a mechanism of action. In addition to this, administration of autologous and allogeneic NK cells after activation and expansion ex vivo is used in the treatment of cancer. Moreover, adoptive transfer of NK cell lines has been tested in humans, and genetically modified NK cells expressing chimeric antigen receptors are being studied in preclinical models for potential use in the clinic.
Download or read book Natural Killer Cells written by Srinivas S. Somanchi and published by Humana Press. This book was released on 2016-05-13 with total page 365 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume contains collection of Natural Killer Cell methodologies relevant for both basic and translational research. These methodologies present new developments in the natural killer (NK) cell field, such as understanding the influence of NK cells metabolism on its function, identifying complexity of NK cell subsets through mass cytometry, and determining the emergence of memory NK cells in murine model of MCMV infection. Methods that study NK cell migration and cytotoxicity through endpoint analysis or live single cell imaging are also discussed. Chapters also describe methods pertaining to translational application of NK cells, such as ex vivo expansion of NK cells on K562 cell lines genetically modified to express either membrane bound IL-15 or membrane bound IL-21, large scale NK cell culture, current techniques for engineering NK cells to express chimeric antigen receptors or chemokine receptors using retroviral vectors, electroporation of mRNA, and the natural phenomenon of trogocytosis. Written in the highly successful Methods in Molecular Biology series format, these chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Cutting edge and thorough, Natural Killer Cells: Methods and Protocols is a valuable resource for researchers who not only want to understand mechanisms that govern NK cell behavior and diversity, but also for those who want to understand how to systematically evaluate NK cells for adoptive immunotherapy applications.
Download or read book Tumor Immunology and Cancer Therapy written by R. H. Goldfarb and published by CRC Press. This book was released on 2020-07-24 with total page 346 pages. Available in PDF, EPUB and Kindle. Book excerpt: Based on a Tumor Immunology Symposium held in Pittsburgh, this work provides comprehensive coverage of the most important aspects of tumor immunology. It reveals novel approaches to the immunotherapy of cancer and presents complex issues in an accessible manner.
Download or read book Gene Editing of IPSC derived Natural Killer NK Cell and Head and Neck Squamous Cell Carcinoma to Improve NK Cell Anti tumor Activity written by Jiyoung Yun and published by . This book was released on 2021 with total page 30 pages. Available in PDF, EPUB and Kindle. Book excerpt: Despite advancements in hematopoietic stem cell transplant (HSCT), graft rejection and graft versus host disease (GvHD) are leading cause of post-transplant mortality. To prevent side effects and to minimize graft rejection, glucocorticoids such as dexamethasone are often administered to patients after transplantation. However, the use of steroids suppresses the proliferation and cytotoxic function of natural killer (NK) cells. To overcome this limitation, I knocked out nuclear receptor subfamily 3 group C member 1 (NR3C1), gene that encodes for the glucocorticoid receptor, on induced pluripotent stem cell (iPSC)-derived NK cells. The NR3C1 knock out (KO) NK cells demonstrated higher proliferation in the presence of high concentration of dexamethasone in vitro while the proliferation of wild type iPSC-NK was inhibited. These studies demonstrate engineered-NR3C1 KO iPSC-NK cells can provide a novel therapeutic benefit in patients undergoing cell therapies that might involve glucocorticoid treatment to ameliorate toxicities. Even with the improvement in iPSC-NK cell therapy, tumor cells become resistant to, and escape NK cell mediated immune surveillance. Previous screening data from our group identified Charged Multivesicular Body Protein 2A (CHMP2A) as a gene that mediates tumor cell resistance to NK cell cytotoxicity. We confirmed that the deletion of CHMP2A in glioblastoma and head and neck squamous cell carcinoma (HNSCC) increased allogeneic NK cell mediated killing in vivo. Here, we better define the role of CHMP2A to regulate anti-tumor immune responses by deletion of CHMP2A in 4MOSC1 and 4MOSC2 HNSCC lines and testing these for tumor development in an immunocompetent syngeneic mouse model.
Download or read book Critical Issues in Head and Neck Oncology written by Jan B. Vermorken and published by Springer Nature. This book was released on 2023-03-27 with total page 361 pages. Available in PDF, EPUB and Kindle. Book excerpt: This is an open access book. With a wealth of exciting data emerging in this rapidly evolving field this book will review the state-of-the-art knowledge with emphasis on multidisciplinary decision and management of head and neck cancer. The book provides significant detail on a wide range of topics including: the role of new targets for treatment, immunotherapy, resistance mechanisms, standardizing molecular profiling programs, and new methods to guide therapeutic approaches. In addition different disease situations are addressed including different treatment approaches in primary disease and in recurrent and/or metastatic disease as well as new developments in pathology, surgery and reconstruction techniques, new systemic therapies in salivary gland cancer, and supportive care and follow-up. All disciplines involved in the treatment of head & neck cancer are covered with a focus on translation into daily practice. The 8th-THNO is designed for medical oncologists, head and neck surgeons, radiation oncologists, otolaryngologists, and other medical professionals involved in the treatment of patients with head and neck cancer.
Download or read book Killer Cell Dynamics written by Dominik Wodarz and published by Springer Science & Business Media. This book was released on 2007-04-05 with total page 226 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book reviews how mathematical and computational approaches can be useful to help us understand how killer T-cell responses work to fight viral infections. It also demonstrates, in a writing style that exemplifies the point, that such mathematical and computational approaches are most valuable when coupled with experimental work through interdisciplinary collaborations. Designed to be useful to immunoligists and viroligists without extensive computational background, the book covers a broad variety of topics, including both basic immunological questions and the application of these insights to the understanding and treatment of pathogenic human diseases.
Download or read book Successes and Challenges of NK Immunotherapy written by Benjamin Bonavida and published by Academic Press. This book was released on 2021-06-23 with total page 540 pages. Available in PDF, EPUB and Kindle. Book excerpt: Successes and Challenges of NK Immunotherapy: Increasing Anti-tumor Efficacy describes the unique therapeutic applications of NK cells to fight cancers and eliminate the bulk and subset of cancer stem cells responsible for metastasis, relapse and recurrences. The book provides information on the development, engineering, mechanisms of action, response to various preclinical models, and applications in various clinical trials. Sections cover the development of highly engineered cytotoxic NK cells, their mechanisms of action, preclinical and clinical applications, the development and application of CAR-NK cells, and new NK-drug conjugates, also emphasizing that activated NK cells can target and kill highly resistant cancer stem cells. Written by the leading experts on NK immunotherapy worldwide, this is a valuable resource for researchers, clinicians and members of the biomedical field who are interested in understanding novel and efficient therapies to fight cancers. Discusses the unique developmental applications of NK immunotherapy against cancers, which differs greatly from other types of immunotherapies Provides up-to-date and highly relevant information through chapters written by the leading researchers in the field Presents a significant number of schematic diagrams for easy understanding and reproducibility
Download or read book An Introduction to Molecular Medicine and Gene Therapy written by Thomas F. Kresina and published by John Wiley & Sons. This book was released on 2004-03-24 with total page 408 pages. Available in PDF, EPUB and Kindle. Book excerpt: An Introduction to Molecular Medicine and Gene Therapy Edited by Thomas F. Kresina, Ph.D. Gene therapy, or the use of genetic manipulation for disease treatment, is derived from advances in genetics, molecular biology, clinical medicine, and human genomics. Molecular medicine, the application of molecular biological techniques to disease treatment and diagnosis, is derived from the development of human organ transplantation, pharmacotherapy, and elucidation of the human genome. An Introduction to Molecular Medicine and Gene Therapy provides a basis for interpreting new clinical and basic research findings in the areas of cloning, gene transfer, and targeting; the applications of genetic medicine to clinical conditions; ethics and governmental regulations; and the burgeoning fields of genomics, biotechnology, and bioinformatics. By dividing the material into three sections - an introduction to basic science, a review of clinical applications, and a discussion of the evolving issues related to gene therapy and molecular medicine-this comprehensive manual describes the basic approaches to the broad range of actual and potential genetic-based therapies. In addition, An Introduction to Molecular Medicine and Gene Therapy: * Covers new frontiers in gene therapy, animal models, vectors, gene targeting, and ethical/legal considerations * Provides organ-based reviews of current studies in gene therapy for monogenetic, multifactoral or polygenic disorders, and infectious diseases * Includes bold-faced terms, key concepts, summaries, and lists of helpful references by subject in each chapter * Contains appendices on commercial implications and a review of the history of gene therapy This textbook offers a clear, concise writing style, drawing upon the expertise of the authors, all renowned researchers in their respective specialties of molecular medicine. Researchers in genetics and molecular medicine will all find An Introduction to Molecular Medicine and Gene Therapy to be an essential guide to the rapidly evolving field of gene therapy and its applications in molecular medicine.
Download or read book Immunoreceptor Signaling written by L. E. Samelson and published by Cold Spring Harbor Perspective. This book was released on 2011 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The behavior of lymphocytes in the immune system depends on encounters with antigens. These bind to immunoreceptors on the surface of T-cells and B-cells, activating a variety of signal transduction pathways that control cell survival, proliferation, differentiation, and effector functions. Written and edited by experts in the field, this collection from Cold Spring Harbor Perspectives in Biology includes contributions covering the structures of the T-cell and B-cell immunoreceptors, the numerous kinases and adaptors that associate with their intracellular tails, and the downstream signaling pathways that lead to transcription of interleukins and other outputs. Other contributions examine the roles of other receptors, co-stimulatory signals, and innate immune responses in regulation of immunoreceptor signaling. The spatial organization of the immunological synapses connecting lymphocytes and antigen-presenting cells is also discussed, along with the role of the cytoskeleton in immunoreceptor function. Computational models of the signaling processes complete the volume, making it essential reading for systems biologists as well as all immunologists and cell biologists interested in understanding how lymphocytes function.
Download or read book Metabolism in Cancer written by Thorsten Cramer and published by Springer. This book was released on 2016-08-24 with total page 272 pages. Available in PDF, EPUB and Kindle. Book excerpt: This textbook presents concise chapters written by internationally respected experts on various important aspects of cancer-associated metabolism, offering a comprehensive overview of the central features of this exciting research field. The discovery that tumor cells display characteristic alterations of metabolic pathways has significantly changed our understanding of cancer: while the first description of tumor-specific changes in cellular energetics was published more than 90 years ago, the causal significance of this observation for the pathogenesis of cancer was only discovered in the post-genome era. The first 10 years of the twenty-first century were characterized by rapid advances in our grasp of the functional role of cancer-specific metabolism as well as the underlying molecular pathways. Various unanticipated interrelations between metabolic alterations and cancer-driving pathways were identified and currently await translation into diagnostic and therapeutic applications. Yet the speed, quantity, and complexity of these new discoveries make it difficult for researchers to keep up to date with the latest developments, an issue this book helps to remedy.
Download or read book Signaling Mechanisms Regulating T Cell Diversity and Function written by Jonathan Soboloff and published by CRC Press. This book was released on 2017-03-27 with total page 258 pages. Available in PDF, EPUB and Kindle. Book excerpt: T cells play a vital role mediating adaptive immunity, a specific acquired resistance to an infectious agent produced by the introduction of an antigen. There are a variety of T cell types with different functions. They are called T cells, because they are derived from the thymus gland. This volume discusses how T cells are regulated through the operation of signaling mechanisms. Topics covered include positive and negative selection, early events in T cell receptor engagement, and various T cell subsets.
Download or read book Advances in Precision Medicine Oncology written by Hilal Arnouk and published by . This book was released on 2021 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Recent advances in precision medicine and immuno-oncology have led to highly specific and efficacious cancer therapies such as monoclonal antibodies and immune checkpoint inhibitors (ICIs). This book provides an up-to-date overview of advances in the field of immuno-oncology. Chapters cover such topics as ICIs and how they mount a robust immune response against cancer cells as well as the response of ICIs to treatment predictive biomarkers and their potential immune-related adverse events (irAEs). Additionally, the book includes a comprehensive review of the powerful FDA-approved therapeutic agent doxorubicin, highlighting the molecular mechanisms behind doxorubicin's drug resistance and critical side effects.
Download or read book Adoptive Immunotherapy written by Burkhard Ludewig and published by Springer Science & Business Media. This book was released on 2008-02-02 with total page 499 pages. Available in PDF, EPUB and Kindle. Book excerpt: An authoritative collection of optimal techniques for producing and characterizing the immunologically active cells and effector molecules now gaining wide use in the clinical treatment of patients. Taking advantage of the latest technologies, the authors present readily reproducible experimental protocols for the study of dendritic cells, T cells, monoclonal antibodies, and bone marrow transplantation. The emphasis is on preclinicical and clinical applications and on the progress of selected approaches in clinical trials. Additional chapters cover the molecular definition of target antigens, mathematical modeling approaches to immunotherapy, and the utilization of regulatory T cells. The protocols make it possible to study the adoptive transfer of tailored antigen-specific immune cells and to improve the clinical application of adoptive immunotherapy.
