Developing Costimulatory Molecules For Immunotherapy Of Diseases

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

Cancer is one of the most prominent causes of mortality in children and adults causing about 9 million deaths annually, is a major health problem worldwide. The transformation of normal cells to cancer cells may arise due to dysregulation of oncogenes, tumor suppressors and/or stability genes. These transformed cells are sensed by the cells of the immune system, especially T cells, through specific receptors for an effective immune response. But unfortunately even after the interaction with T cells, an effective immune response is not generated. Considering the importance of costimulation in the regulation of immune responses against relapsed cancer, the manipulation of this pathway to increase immunity, regress the growth, augment the expression of pro-apoptotic molecules and induce the apoptosis of lymphomas represents a potential therapeutic approach. This novel strategy of costimuilation activation/inhibition can be effectively exploited to develop immunotherapy either using humanized antibodies against CD80, CD86 and CD40 or CD28 fusogenic proteins for the treatment of intracellular pathogens like M. tuberculosis, HIV, L. donovani, T. cruzi, etc. This strategy can also be used as an alternative strategy or in combination with the drugs. Since this approach is based on modulating the immune system of the hosts rather than targeting the pathogen; hence it significantly diminishes chance of emergence of drug resistant strains of pathogens and if applied properly, may overcome the rising menace of infectious diseases. The potent role of costimulatory molecules is aptly established in the optimum activation of T cells and APCs; the cells that play a cardinal role in curbing the infections. Hence, immunotherapy involving costimulatory molecules can be a breakthrough strategy to treat various diseases, minimizing side effects inflicted by drug therapies and in restricting the emergence of drug resistance.

Clinicians, patients and scientists, alike, have been battling cancer for over several decades; however, patient outcomes have not significantly improved over the years with conventional therapies. In recent years, this has caused researchers to look for a change in the status quo, and, the awareness of the human immune system, which has an intrinsic mechanism to control microbial pathogens and dysfunctional self-tissues, has triggered scientists to look for new modes of cancer therapy. Cancer Immunotherapy has become a major research field as a result of these efforts, gaining some recognition for notable breakthroughs in cancer patient prognosis. Frontiers in Cancer Immunology collectively presents the methods which have been studied and used in cancer immunotherapy based on the different components of human immune system. The series will give clinicians and immunologists a roadmap of current trends in all branches of cancer immunology. This volume lists the major immune system components (such as T cells and NK cells and associated antigens/antibodies) which have been demonstrated to limit the growth of or kill tumor cells. Relevant applications in cancer therapy are also included in addition to a general introduction to engineered as well as targeted cancer immunotherapies (cancer vaccines).

Cancer is one of the most prominent causes of mortality in children and adults causing about 9 million deaths annually, is a major health problem world-wide. The transformation of normal cells to cancer cells may arise due to dysregulation of oncogenes, tumour suppressers and/or stability genes. These transformed cells are sensed by the cells of the immune system, especially T cells, through specific receptors for an effective immune response. But unfortunately even after the interaction with T cells, an effective immune response is not generated. Considering the importance of costimulation in the regulation of immune responses against relapsed cancer, the manipulation of this pathway to increase immunity, regress the growth, augment the expression of pro-apoptotic molecules and induce the apoptosis of lymphomas represents a potential therapeutic approach. This novel strategy of costimuilation activation/inhibition can be effectively exploited to develop immunotherapy either using humanised antibodies against CD80, CD86 and CD40 or CD28 fusogenic proteins for the treatment of intracellular pathogens like M. tuberculosis, HIV, L donovani, T cruzi, etc. This strategy can also be used as an alternative strategy or in combination with the drugs. Since this approach is based on modulating the immune system of the hosts rather than targeting the pathogen; hence it significantly diminishes chance of emergence of drug resistant strains of pathogens and if applied properly, may overcome the rising menace of infectious diseases. The potent role of costimulatory molecules is aptly established in the optimum activation of T cells and APCs; the cells that play a cardinal role in curbing the infections. Hence, immunotherapy involving costimulatory molecules can be a breakthrough strategy to treat various diseases, minimising side effects inflicted by drug therapies and in restricting the emergence of drug resistance.

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.

Proteomics: A Promising Approach for Cancer Research provides an updated overview of scientific knowledge, achievements and findings in the field of cancer proteomics. The book discusses topics such as the use of proteomics in cancer biology and drug discovery, its role in surgical oncology, applications of mass spectrometry, target proteomics, single-cell proteomics, and next-generation proteomics. In addition, it discusses proteomics and phosphor-proteomics in cancer precision medicine; translation of proteomics research into clinical application; and challenges and future developments of the field. This will be a valuable resource for cancer researchers, oncologists, graduate students, and members of biomedical field who are interested in the potential of proteomics in cancer research and treatment. The field of cancer proteomics is very dynamic, with emerging trends related to clinical solutions developed in recent years, therefore this book's content helps readers get up-to-speed on the topic to easily apply learnings into their research or clinical practice. Provides up-to-date information on current cancer proteomics research developed globally Presents basic research aspects to clinical implications of proteomics on cancer diagnosis and potential treatments Discusses challenges and future developments of the field to leverage further research and applicability in clinical setting

Cancer accounts for nearly one-quarter of deaths in the United States, exceeded only by heart diseases. Despite the development of various strategies to treat cancer, it remains one of the most deadly diseases worldwide due to the limited effects of treatments available. The limited efficacy of these current treatment modalities, such as surgery, radiotherapy, and chemotherapy, are often due to their association with adverse side effects arising from lack of specificity for tumors, and most importantly their failure of eliminating residual and micro-metastatic tumors, which can lead to recurrences. Therefore, there is a dire need to develop tumor-specific therapies that not only eliminate primary tumors, but also micro-metastasis and prevent recurrences. In this regard, therapeutic cancer vaccines based on tumor-associated antigens (TAAs) has evolved as a promising approach due to their safety profile, ease of production, storage, transportation, administration to a broad patient population and most importantly establishment and/or maintenance of long-term immunological memory critical for the control of recurrences, a major cause of cancer death. However, despite theoretical promise, development of therapeutic cancer vaccines has been facing numerous set-backs mostly due to the weak immunogenicity of T AAs, tolerance to self-T AAs and various immune evasion mechanisms employed by progressing tumors. Therefore, we hypothesized that use of natural costimulatory ligands of TNF family as adjuvant may overcome these limitations due to their effect on cells of innate, adaptive, and regulatory immunity without any sign of toxicity. The tumor necrosis factor receptor (TNFR)/TNF superfamily represents a crucial group of costimulatory receptor/ligands as most of the receptors of this family are inducibly expressed on various immune cells. Costimulatory receptors that are inducibly expressed or upregulated on activated T cells may serve as preferred targets for immunomodulation due to their potential to selectively target antigen-experienced T cells for expansion, survival, and establishment of long-term immunological memory. Among these family members, 4-1BB/4-1BBL signaling has recently been much appreciated as its signaling provides the essential survival signals, particularly in CD8+ T cells. 4-1BB signaling into T cells allows CD8+ T cell expansion, cytokine production, development of CTL effector function, and prevention of apoptotic cell death by up-regulating anti-apoptotic Bcl-xL and Bcl-2 molecules. As the aim of tumor immunotherapy is to generate long-lasting immune response, particularly CD8+ T cell specific response, for the destruction of tumor cells, in this project, we focused on the utilization of 4-1 BBL either alone or in combination with other immunomodulators, as a component of TAA-based subunit vaccines and tested its efficacy in preclinical mice tumor models. First, we report that a single immunization with a therapeutic vaccine formulation containing novel form of soluble SA-4-1BBL, and survivin (SVN), a bona fide self antigen, resulted into the eradication of SVN-expressing 3LL tumors in 75% of mice in the absence of autoimmunity. The efficacy of vaccine was further improved to complete tumor eradication with an additional vaccination 6 days after the first vaccination. CD8+ T cells and NK cells effector function was found to be critical for the efficacy of vaccine, but not the CD4 + T cells. Next, we tested the vaccine formulation containing combination of SA-4-IBBL and toll-like receptor 4 agonist monophosphoryl lipid A (MPL) with distinct mechanisms of action as a novel adjuvant system. A single immunization with both adjuvants and HPV E7 protein resulted in eradication of 100% of E7 expressing TC-1 tumors. Combined adjuvants had better therapeutic efficacy over the individual adjuvants, while SA-4-1BBL monotherapy outperformed MPL, 80% vs. 50%. Similarly, a single vaccination with SVN resulted in control/eradication of established 3LL pulmonary metastases that was further improved by a booster injection. The therapeutic efficacy of combined adjuvants as well as SA-4-1BBL as monotherapy was achieved in the absence of detectable toxicity and correlated with enhanced CD8+ T cell function and increased intratumoral CD8+ T effector/CD4+FoxP3+ T regulatory cell ratio. In marked contrast, vaccination with MPL as monotherapy resulted in an unfavorable intratumoral CD8+ T effector/CD4+FoxP3+ T regulatory cell ratio that played a definitive role in vaccine efficacy. Depletion of T regulatory cells improved MPL efficacy to 100%, whereas elimination of CD8+ T cells totally abrogated the efficacy of combined adjuvants. In last, we report that combination of SA-4-1BBL and SA-OX40L, another member of TNF ligand family, was also able to eradicate TC-I tumors in 100% of mice. This efficacy was mainly dependent on CD8+ T cells as depletion of these cells completely abrogated the efficacy. Importantly, combination of these two ligands was also able to eradicate a 3-4 mm established tumors in 50% of mice. Taken together, these data provide important mechanistic insight into the mode of action of SA-4-1BBL alone or in combination either MPL or SA-OX40L adjuvants and demonstrate its utility as a novel adjuvant system for the development of therapeutic TAA-based subunit cancer vaccines with significant clinical implications. These data also shed lights into the mode of action of MPL and SA-OX40L as a part of vaccine adjuvant systems and set the stage for their utilization in the development of new vaccine strategies.

The Cytokines of the Immune System catalogs cytokines and links them to physiology and pathology, providing a welcome and hugely timely tool for scientists in all related fields. In cataloguing cytokines, it lists their potential for therapeutic use, links them to disease treatments needing further research and development, and shows their utility for learning about the immune system. This book offers a new approach in the study of cytokines by combining detailed guidebook-style cytokine description, disease linking, and presentation of immunologic roles. Supplies new ideas for basic and clinical research Provides cytokine descriptions in a guidebook-style, cataloging the origins, structures, functions, receptors, disease-linkage, and therapeutic potentials Offers a textbook-style view on the immune system with the immunologic role of each cytokine

Cytokine and Chemokine Networks in Cancer" provides a comprehensive exploration of the roles of cytokines and chemokines in cancer biology. It offers valuable insights into their diagnostic, prognostic, and therapeutic implications, making it a valuable resource for researchers, clinicians, and students interested in the field of cancer immunology and therapy. This book illustrates the importance and significance of the cytokine and chemokine signaling networks in tumor development and progression. It describes the complex networks mediated by cytokine and chemokine receptors promoting tumor cell proliferation, site-directed metastasis, and activation of angiogenic switch in tumor cells. The books also shed light on the heterogeneity of cytokines and chemokine in solid malignancies and their impact on tumor progression and therapeutic outcomes. The chapters provide current information about the types of cytokine-chemokine interactions in promoting cancer stem cell-like characteristics, epithelial to mesenchymal transition, and modulation of the tumor microenvironment. The significance of the complex interactions in cancer biology in the light of therapeutic resistance is also highlighted. The chapters also describe recent advancements in the therapeutic potential of targeting the pro-tumor cytokine and chemokine networks and limiting tumor cell metastasis. Finally, the book also provides a comprehensive yet representative description of a large number of challenges associated with targeting these vital chemokine-cytokine networks. Given its content, the book provides valuable information for researchers in the field of cancer biology and molecular medicine.

Considering the global emerging human pathogenic microbial diseases and trends, Human Pathogenic Microbes is framed to provide deep insights into the epidemic and emerging bacterial and fungal infections and diseases in humans. It presents novel, up-to-date, and cutting-edge knowledge regarding various human pathogenic microbes, their associated drug resistance mechanisms, and different diseases caused by them. Human Pathogenic Microbes reflects the current research and development on the evolution of bacterial and fungal drug resistance: different bacterial and fungal antimicrobial drug resistance mechanisms along with their biological and molecular aspects. In a nutshell, Human Pathogenic Microbes describes a various bacterial and fungal diseases caused by different human pathogenic microbes employing different drug resistance mechanisms and processes. It also highlights the novel emerging approaches (Immunological and combinatorial) that will aid to fight against such bacterial and fungal pathogens. Provides a brief but thorough and recent knowledge of various human pathogenic microbes, their associated drug resistance mechanisms, and different diseases caused by them Describes the different aspects of fungal, bacterial and antimicrobial resistance Addresses novel antimicrobial agents and approaches