Chimeric Antigen Receptor T-Cell Therapies for Cancer

From patient referral to post-therapy management, Chimeric Antigen Receptor (CAR) T-Cell Therapies for Cancer: A Practical Guide presents a comprehensive view of CAR modified T-cells in a concise and practical format. Providing authoritative guidance on the implementation and management of CAR T-cell therapy from Drs. Daniel W. Lee and Nirali N. Shah, this clinical resource keeps you up to date on the latest developments in this rapidly evolving area. Covers all clinical aspects, including patient referral, toxicities management, comorbidities, bridging therapy, post-CAR monitoring, and multidisciplinary approaches to supportive care. Includes key topics on associated toxicities such as predictive biomarkers, infections, and multidisciplinary approaches to supportive care. Presents current knowledge on FDA approved CAR T-cell products as well as developments on the horizon. Editors and authors represent leading investigators in academia and worldwide pioneers of CAR therapy.

From patient referral to post-therapy management, Chimeric Antigen Receptor (CAR) T-Cell Therapies for Cancer: A Practical Guide presents a comprehensive view of CAR modified T-cells in a concise and practical format. Providing authoritative guidance on the implementation and management of CAR T-cell therapy from Drs. Daniel W. Lee and Nirali N. Shah, this clinical resource keeps you up to date on the latest developments in this rapidly evolving area. Covers all clinical aspects, including patient referral, toxicities management, comorbidities, bridging therapy, post-CAR monitoring, and multidisciplinary approaches to supportive care. Includes key topics on associated toxicities such as predictive biomarkers, infections, and multidisciplinary approaches to supportive care. Presents current knowledge on FDA approved CAR T-cell products as well as developments on the horizon. Editors and authors represent leading investigators in academia and worldwide pioneers of CAR therapy.

Basics of Chimeric Antigen Receptor (CAR) Immunotherapy presents the latest on how T cell adoptive immunotherapy has progressed in its ultimate goal of curing metastatic malignant cancers. Recent clinical data obtained with checkpoint receptor blockade inhibitors and chimeric antigen receptor (CAR) therapy has been especially promising, thus generating renewed hope that we may be on the verge of finally curing cancer. Over the years, huge progress has been made in controlling several stage IV metastasized cancers through the clinical application of checkpoint receptor inhibitory drugs and CAR-Therapy that has seen unprecedented interest in the immunotherapy field. Presents the first book to provide a basic understanding of chimeric antigen receptor (CARs) design, production and clinical application protocols Provides unique authority as the editor has worked directly with CARs Discusses the challenges encountered in actual clinical trials and how these challenges can be overcome Includes a full chapter on various challenges researchers should expect to encounter in the CAR-therapy field

Chimeric antigen receptor (CAR) T cell therapies for leukemia (e.g. tisagenlecleucel) and lymphoma (e.g. axicabtagene ciloleucel) have recently received regulatory approval in the United States. Phase I/II trials have demonstrated complete remission of refractory or relapsed tumors in 50% - 94% patients. However, the clinical successes of engineered T cells for the treatment of solid malignancies have thus far been few and far between. Furthermore, several instances of severe and lethal toxicities have arisen due to on-target, off-tumor recognition of antigen by T cell products. Recent advances in phase I trials for solid tumors, as well as in pre-clinical models, have revealed several variables that will be important to consider for the successful use of CAR-T cells in treating solid tumors. These variables include (i) regional versus systemic delivery; (ii) scFv versus ligand interactions; (iii) antigen loss versus escape; (iv) epitope spreading and (v) checkpoint expression on immune cells or tumor cells. Also, there remains outstanding mechanistic questions related to why differences exist in the persistence and tonic signaling of second-generation CD28 versus 4-1BB co-stimulated CAR-T cells. In addition, we are now learning the roles of lympho-depleting regimens (and associated toxicities) in modifying the persistence of engineered T cell therapies. A more comprehensive view of CAR-T cell strategies and important advances, both of pre-clinical and clinical evaluations, in solid tumors is necessary to drive these therapies forward.

This volume illustrates the salient aspects of cancer biology relevant to the successful implementation of immunotherapy. Topics include enhancement of antigen-specific immune responses by anti-cancer vaccines, modulation of the function of T cells within the tumor microenvironment, and the effects of genetic, epigenetic, developmental, and environmental determinants on T cell function. Other topics covered include the ex vivo expansion of T or other immune cells and their genetic modification or reprogramming to increase their ability to survive and expand when adoptively transferred back to the patients. Specific attention is devoted to the genetic manipulation of T cells through the introduction of re-directed T cell receptors, chimeric antibody receptors, and other genetic manipulation aimed at improving their effectiveness as anti-cancer agents. Furthermore, the revolutionary role of checkpoint inhibitors and their potential in combination with other immunotherapeutic approaches or with standard chemo and radiation therapy are extensively discussed.

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.

Part I- Understanding Cancer Immunotherapy: A brief Review. Immunotherapy, also called biologic therapy, is a type of cancer treatment that boosts the body's natural defenses to fight cancer. It uses substances made by the body or in a laboratory to improve or restore immune system function. Immunotherapy may work by: Stopping or slowing the growth of cancer cells Stopping cancer from spreading to other parts of the body Helping the immune system work better at destroying cancer cells There are several types of immunotherapy, including: Monoclonal antibodies and tumor-agnostic therapies Non-specific immunotherapies Oncolytic virus therapy T-cell therapy Cancer vaccines Part II- “What is Chimeric Antigen Receptor (CAR) T- Cell Therapy?” An Emerging Cancer Treatment Modality. Chimeric antigen receptor (CAR) T-cell therapy is an emerging cancer treatment modality in which the patients’ own immune cells are collected, genetically engineered to recognize a tumor-related target, expanded in vitro, and then reinfused to produce responses and prevent progression in a variety of malignancies (ie, adoptive cell transfer) Several types of adoptive cell transfer(ACT) are under investigation, but CAR T-cell therapy is the first to enter clinical practice. Like other technologies, CAR-T cell therapy has undergone a long development process in the past. Chimeric antigen receptor- (CAR-) T cell therapy is one of the most recent innovative immunotherapies and is rapidly evolving. At present, CAR-T cell therapy is developing rapidly, and many clinical trials have been established on a global scale, which has great commercial potential. I have endeavored to compile this E- Booklet into Two Parts i.e. Part I & Part II for better understanding of Chimeric antigen receptor (CAR) T-cell therapy, an emerging cancer treatment modality. In Part I, an effort has been made to describe Cancer Immunotherapy briefly whereas in Part II know about of CAR T-Cell Therapy-the first to enter clinical practice- has been embodied. Further it is attempted to describe toxicity of CAR-T cell therapy briefly and future development and opportunities for immunotherapy. …Dr. H. K. Saboowala. M.B.(Bom) .M.R.S.H.(London)

Chimeric antigen receptor (CAR) T cell therapy has emerged as an effective new cancer treatment that genetically reprograms a patient’s T cells to recognize an epitope specifically expressed on the surface of cancer cells and trigger cytotoxic action against those cancer cells. This therapy has been especially effective in the treatment of CD19+ hematologic malignancies. However, the manufacturing of these autologous cell therapies requires laborious processing steps that present multiple challenges and opportunities for innovation, described in Chapter 1. The current manufacturing system requires extensive use of biologic reagents including antibody-coated magnetic beads for manipulation and expansion, and retroviruses for genetic modification of ex vivo cultured T cells. In this work, three classes of synthetic biomaterials are developed to improve and study the ex vivo expansion and genetic modification of primary human T cells. In Chapter 2, we describe the development of cell-templated supported lipid bilayers as a platform for studying the effect of activation particle design on polyclonal T cell expansion and differentiation. Chapter 3 describes work towards identifying synthetic peptide and aptamer targeting ligands for T cell activation through library screening techniques. In Chapters 4 and 5, we report the use of cationic polymers of defined architecture for non-viral gene delivery to T cells and study the underlying barriers to improved gene delivery in T cells. The major findings from this work are summarized in Chapter 6 where we also make recommendations for future applications and directions of this work.

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Histone 3 K27M mutated diffuse midline glioma (H3K27M DMG) is a universally fatal pediatric brain tumor. Despite improved understanding of the molecular origins of this disease, translations to improvement in clinical outcomes have yet to materialize. To date, there has been little target exploration for immunotherapy applications in H3K27M DMG. In this thesis, I describe my work that elucidated substantial preclinical efficacy of chimeric antigen receptor (CAR)-bearing T cells targeting the disialoganglioside GD2 as an immunotherapy regimen in patient-derived orthotopic xenograft models of H3K27M DMG. Single-dose systemic administration of GD2-4-1BB-CAR T cells in multiple orthotopic xenograft models of H3K27M DMG achieves potent and lasting antitumor efficacy, including tumor clearance by in vivo bioluminescence imaging and follow-up histology. Treatment-associated toxicity was transient and generally tolerated during the period of peak anti-tumor activity in brainstem orthotopic xenografts. If these results are predictive of human response, GD2-directed CAR T cell therapy in the setting of careful clinical management could have a transformative impact upon H3K27M DMG outcomes. In part two of this thesis, I present data revealing a brain-wide map of afferent neuronal connectivity to oligodendrocyte precursor cells (OPCs). Neurons form bona fide synapses with oligodendrocyte precursor cells (OPCs), but the circuit context of these neuron to OPC synapses remains incompletely understood. Using monosynaptically-restricted rabies virus tracing of OPC afferents, I identified extensive afferent synaptic inputs to OPCs residing in secondary motor cortex and underlying corpus callosum of adult mice. These inputs primarily arise from functionally-interconnecting cortical areas and thalamic nuclei, demonstrating that OPCs in motor-associated territories have synaptic access to brain-wide projection networks engaged in planning and execution of motor tasks. This circuit map is a foundational tool for future studies of context-specific neuron-OPC synapse function.

Developing Costimulatory Molecules for Immunotherapy of Diseases highlights the novel concept of reverse costimulation and how it can be effectively exploited to develop immunotherapy using either humanized antibodies against CD80, CD86, and other costimulatory molecules or CD28 fusinogenic proteins in the treatment of diseases, including allergies, asthma, rheumatoid arthritis, multiple sclerosis, lupus nephritis, severe psoriasis, vulgaris tuberculosis, thopoid, transplantation therapeutic, cancer, and inflammation. The text aims to provide the latest information on the complex roles and interactions within the CD28 and B7 costimulatory families, with the hope that targeting these families will yield new therapies for the treatment of inflammation, autoimmunity, transplantation, cancer, and other infectious diseases. Highlights the novel concept of reverse costimulation and how it can be effectively exploited to develop immunotherapy Provides the latest information on the complex roles and interactions within the CD28 and B7 costimulatory families Targets new therapies for the treatment of inflammation, autoimmunity, transplantation, cancer, and other infectious diseases

This Open Access edition of the European Society for Blood and Marrow Transplantation (EBMT) handbook addresses the latest developments and innovations in hematopoietic stem cell transplantation and cellular therapy. Consisting of 93 chapters, it has been written by 175 leading experts in the field. Discussing all types of stem cell and bone marrow transplantation, including haplo-identical stem cell and cord blood transplantation, it also covers the indications for transplantation, the management of early and late complications as well as the new and rapidly evolving field of cellular therapies. This book provides an unparalleled description of current practices to enhance readers’ knowledge and practice skills.

In this book, experts in the field express their well-reasoned opinions on a range of complex, clinically relevant issues across the full spectrum of cell and gene therapies with the aim of providing trainee and practicing hematologists, including hematopoietic transplant physicians, with information that is relevant to clinical practice and ongoing research. Each chapter focuses on a particular topic, and the concise text is supported by numerous working tables, algorithms, and figures. Whenever appropriate, guidance is provided regarding the availability of potentially high-impact clinical trials. The rapid evolution of cell and gene therapies is giving rise to numerous controversies that need to be carefully addressed. In meeting this challenge, this book will appeal to all residents, fellows, and faculty members responsible for the care of hematopoietic cell transplant patients. It will also offer a robust, engaging tool to aid vital activities in the daily work of every hematology and oncology trainee.

A guide to state-of-the-art cancer immunotherapy in translational cancer research A volume in the Translational Oncology series, Immunotherapy in Translational Cancer Research explores the recent developments in the role that immunotherapy plays in the treatment of a wide range of cancers. The editors present key concepts, illustrative examples, and suggest alternative strategies in order to achieve individualized targeted therapy. Comprehensive in scope, Immunotherapy in Translational Cancer Research reviews the relevant history, current state, and the future of burgeoning cancer-fighting therapies. The book also includes critical information on drug development, clinical trials, and governmental resources and regulatory issues. Each chapter is created to feature: development of the immunotherapy; challenges that have been overcome in order to scale up and undertake clinical trials; and clinical experience and application of research. This authoritative volume is edited by a team of noted experts from MD Anderson Cancer Center, the world’s foremost cancer research and care center and: Offers a comprehensive presentation of state-of-the-art cancer immunotherapy research that accelerates the pace of clinical cancer care Filled with the concepts, examples, and approaches for developing individualized therapy Explores the breath of treatments that reflect the complexity of the immune system itself Includes contributions from a panel international experts in the field of immunotherapy Designed for physicians, medical students, scientists, pharmaceutical executives, public health and public policy government leaders and community oncologists, this essential resource offers a guide to the bidirectional interaction between laboratory and clinic immunotherapy cancer research.

Chemotherapy and Immunotherapy Guidelines and Recommendations for Practice features 26 chapters examining multiple categories of cancer-care agents, including chemotherapy, immunotherapy, molecularly targeted agents, and hormone therapy.

Second Generation Cell and Gene-Based Therapies: Biological Advances, Clinical Outcomes, and Strategies for Capitalisation serves as the only volume to the market to bridge basic science, clinical therapy, technology development, and business in the field of cellular therapy/cytotherapy. After more than two decades of painstaking fundamental research, the concept of therapeutic cells (stem cells, genes, etc.), beyond the concept of vaccines, is reaching clinical trial, with mounting confidence in the safety and efficacy of these products. Nonetheless, numerous incremental technical advances remain to be achieved. Thus, this volume highlights the possible R&D paths, which will ultimately facilitate clinical delivery of cutting edge curative products. The next waves of innovation are reviewed in depth for hematopoietic stem cells, mesenchymal stem cells, tissue engineering, CAR-T cells, and cells of the immune system, as well as for enabling technologies such as gene and genome editing. Additionally, deep dives in product fundamentals, history of science, pathobiology of diseases, scientific and technological bases, and financing and technology adoption constraints are taken to unravel what will shape the cytotherapy industry to the horizon 2025 and beyond. The outcome is not simply a scientific book, but a global perspective on the nascent field combining science, business, and strategic fundamentals. Helps readers learn about the most current trends in cell-based therapy, their overall effectiveness from a clinical prospective, and how the industry is moving therapies forward for capitalization "Perspectives" section at the end of each chapter summarizes key learnings, hypotheses, and objectives highlighted and combines scientific and business insights Edited and authored by scientists representing both basic and clinical research and industry, presenting a complete story of the current state and future promise of cellular therapies

In this book, leading experts in cancer immunotherapy join forces to provide a comprehensive guide that sets out the main principles of oncoimmunology and examines the latest advances and their implications for clinical practice, focusing in particular on drugs with FDA/EMA approvals and breakthrough status. The aim is to deliver a landmark educational tool that will serve as the definitive reference for MD and PhD students while also meeting the needs of established researchers and healthcare professionals. Immunotherapy-based approaches are now inducing long-lasting clinical responses across multiple histological types of neoplasia, in previously difficult-to-treat metastatic cancers. The future challenges for oncologists are to understand and exploit the cellular and molecular components of complex immune networks, to optimize combinatorial regimens, to avoid immune-related side effects, and to plan immunomonitoring studies for biomarker discovery. The editors hope that this book will guide future and established health professionals toward the effective application of cancer immunology and immunotherapy and contribute significantly to further progress in the field.

Since the original publication of Allogeneic Stem Cell Transplantation: Clinical Research and Practice, Allogeneic hematopoietic stem cell transplantation (HSC) has undergone several fast-paced changes. In this second edition, the editors have focused on topics relevant to evolving knowledge in the field in order to better guide clinicians in decision-making and management of their patients, as well as help lead laboratory investigators in new directions emanating from clinical observations. Some of the most respected clinicians and scientists in this discipline have responded to the recent advances in the field by providing state-of-the-art discussions addressing these topics in the second edition. The text covers the scope of human genomic variation, the methods of HLA typing and interpretation of high-resolution HLA results. Comprehensive and up-to-date, Allogeneic Stem Cell Transplantation: Clinical Research and Practice, Second Edition offers concise advice on today's best clinical practice and will be of significant benefit to all clinicians and researchers in allogeneic HSC transplantation.