Download or read book Enhancement of T Cell Responses Through CTLA 4 Blockade Combination Therapy in a Mouse Model of Prostate Cancer written by Rebecca Waitz and published by . This book was released on 2008 with total page 370 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book CTLA 4 Blockade Based Immunotherapy in Prostate Cancer written by and published by . This book was released on 2005 with total page 8 pages. Available in PDF, EPUB and Kindle. Book excerpt: CTLA-4 is an inhibitory molecule on T cells down regulation. Granulocyte-macrophage colony stimulating factor (GM-CSF) is a growth and survival factor for dendritic cells. The safety of combining GM-CSF with CTLA-4 blockade in prostate cancer patients is being investigated in an ongoing phase 1 trail. Sequential cohorts of 3-6 patients receive GM-CSF 250 ug/m2/d subcutaneously on days 1-14 of a 28-day cycle with escalating doses of anti-CTLA antibody on day 1 of each cycle x4. Patients are monitored for clinical autoimmunity with T cell phenotyping performed. Twelve patients have been treated to date. Dose-limiting toxicity (DLT) was not observed in the initial CTLA-4 antibody dose level. Two DLTs, consisting of a vertebrobasilar TIA possibly related to therapy and a generalized rash requiring steroids were observed in the second and third dose levels respectively, resulting in expansion of each to 6 patients. No laboratory evidence of autoimmunity has been observed in any patient. Expansion of monocytes/dendritic cells and upregulation of PBMC activation markers have been seen, consistent with known GM-CSF effect. CTLA-4 blockade and GM-CSF has demonstrated preliminary safety in advanced prostate cancer. Accrual and immunologic analyses are ongoing.
Download or read book Immunotherapy of Melanoma written by Anand Rotte and published by Springer. This book was released on 2016-12-19 with total page 434 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book focusses on the different types of immunotherapeutics that are currently being used and developed for the treatment of melanoma. In recent years, immunotherapy has revolutionized the treatment of metastatic melanoma and other types of cancer. Discussing treatment options for melanoma and the success of immunotherapy along with the challenges of immunotherapy, this book covers epidemiology, susceptibility genes, and treatment recommendations from Society for Immunotherapy of Cancer, as well as immune based therapies such as aldesleukin, Intron-A, Sylatron, Yervoy, Opdivo, Keytruda, Imlygic, DC vaccines and adoptive cell therapy. The detailed information included on the key immune cells involved in anti-tumor immune response and immune-inhibitory mechanisms in tumor microenvironment will aid the understanding of tumor immunology. Both academic as well as industry-based researchers, developing novel anti-cancer therapies, will also benefit from the details of promising molecular targets and immunotherapeutic strategies under investigation. With 132 illustrations including synopsis tables for important information, over 1200 references (majority of which are openly accessible) and details of more than 150 ongoing clinical trials, this book is a valuable source of information for health care providers as well as cancer biologists interested in learning about melanoma and the significant advances made by immunotherapy.
Download or read book A Phase II Immunotherapeutic Trial Combination Androgen Ablative Therapy and CTLA 4 Blockade as a Treatment for Advanced Prostate Cancer written by and published by . This book was released on 2003 with total page 8 pages. Available in PDF, EPUB and Kindle. Book excerpt: The induction of tumor-specific T cells remains a primary obstacle to immunotherapeutic approaches for most cancers including prostate cancer. This difficulty has been largely ascribed to mechanisms for tumor evasion of the immune system and host-imposed restrictions (collectively referred to as tolerance) that prevent cross-reactive autoimmunity against the parent tissues from which tumors arise. Limitations in techniques to identify novel and truly immunogenic prostate-specific antigens and efficient methods to modify autologous tissues for vaccine preparation have further constrained approaches to develop immune-based therapies for prostate cancer. Hence, relatively straightforward manipulations that induce specific T cell responses against prostate tumors or epithelial tissues, especially in vivo, might ultimately prove valuable for prostate cancer immunotherapy. This study explores combined androgen ablation (AA) + CTLA-4 blockade immunotherapy as a means of potentiating T cell-mediated responses against prostate tumors to improve overall treatment of advanced prostate cancer.
Download or read book Enhancing T Cell Immunity in Tumor Immunotherapy written by Xiaozhou Fan and published by . This book was released on 2013 with total page 212 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) is a crucial inhibitory molecule to restrain T cell functions. CTLA-4 blockade with a monoclonal antibody (anti-CTLA-4) induces anti-tumor responses in a subset of patients and has been approved by the FDA as standard therapy for melanoma. We recently identified inducible costimulator (ICOS) as a crucial player in the antitumor effects of CTLA-4 blockade. We now show that concomitant CTLA-4 blockade plus ICOS engagement by tumor cell vaccines engineered to express ICOS-ligand enhanced anti-tumor immune responses in both quantity and quality and significantly improved rejection of established melanoma and prostate cancer in mice. This study provides strong evidence to support future combinatorial approaches incorporating anti-CTLA-4 plus ICOS engagement in the clinic. We explored another strategy to enhance anti-tumor response by targeting the migration of regulatory T cells into the tumor. We proposed certain chemokines and their cognate receptors play key roles in this process. Chemokine receptors CCR4 and CCR8 are preferentially expressed by regulatory T cells in the tumor where their ligands CCL1 and CCL17 are upregulated. CCL17 was able to induce specific migration of regulatory T cells from tumor-bearing mice, and we identified a CD11b + F4/80 + Gr-1 - population in the tumor as the major source of CCL17. With an in vivo migration assay and a bone marrow chimera model, we demonstrated that CCR4 is required for the migration of regulatory T cells to the vaccine site. Lastly, we found that transfer of small numbers of naive tumor-reactive CD4 T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation. Surprisingly, CD4 T cells developed cytotoxic activity, and tumor rejection was dependent on class II-restricted recognition of tumors by tumor-reactive CD4 T cells. Furthermore, blockade of the CTLA-4 on transferred CD4 T cells resulted in greater expansion of effector T cells, diminished accumulation of regulatory T cells, and superior antitumor activity. These findings suggest a novel potential therapeutic role for cytotoxic CD4 T cells and CTLA-4 blockade in cancer immunotherapy, and the potential advantages of differentiating tumor-reactive CD4 cells in vivo.
Download or read book Developments in T Cell Based Cancer Immunotherapies written by Paolo A. Ascierto and published by Humana Press. This book was released on 2015-11-26 with total page 315 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.
Download or read book Cancer Immunotherapy written by Margaret K. Callahan and published by Elsevier Inc. Chapters. This book was released on 2013-06-04 with total page 40 pages. Available in PDF, EPUB and Kindle. Book excerpt: Ipilimumab is the first drug to show a survival benefit for patients with advanced melanoma and was approved by the US Food and Drug Administration in March of 2011. Ipilimumab enhances antitumor immunity by enhancing T-cell function by blocking the negative regulatory molecule, cytotoxic T-lymphocyte antigen 4 (CTLA-4). Unlike traditional cancer therapy, ipilimumab’s effects may be delayed and occur after initial apparent disease progression. A distinct set of side effects have been described, and ongoing efforts continue to characterize immunologic changes associated with patients who benefit from therapy. Efforts to characterize ipilimumab’s clinical activity in malignancies other than melanoma are ongoing.
Download or read book CTLA 4 Challenges limitations and future perspective in cancer immunotherapy written by Sina Taefehshokr and published by Frontiers Media SA. This book was released on 2023-10-05 with total page 144 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Combinatorial Approaches to Enhance Anti Tumor Immunity Focus on Immune Checkpoint Blockade Therapy written by Patrik Andersson and published by Frontiers Media SA. This book was released on 2019-12-27 with total page 316 pages. Available in PDF, EPUB and Kindle. Book excerpt: The immune system harbors great potential for controlling and eliminating tumors. Recent developments in the field of immuno-oncology has led to unprecedented clinical benefits for a broad spectrum of solid tumors. However, immunotherapy (IT) approaches currently have several limitations including (i) low response rate; (ii) development of resistance and (iii) causing severe immune-related adverse effects (IrAEs), which underline the importance of adequate patient selection. Importantly, IT holds promising synergistic potential when combined with standard-of-care chemotherapy, radiotherapy (RT) and anti-angiogenic therapy (AAT) as part of multi-modal oncologic treatment regimes. Published data suggest that there are potential synergy between RT and AAT, which ultimately could help potentiate the response to IT. However, the complex interactions between RT and IT and/or AAT remain poorly understood. Many research questions including optimal timing, scheduling and dosing, as well as patient selection and side effects of combined therapy approaches, remain to be addressed. This Research Topic aims to give a comprehensive overview of the current field with particular emphasis on the future outlook of RT and AAT as complementary approaches to improve IT in solid tumors.
Download or read book Melanoma written by Howard L. Kaufman and published by Springer. This book was released on 2015-11-24 with total page 413 pages. Available in PDF, EPUB and Kindle. Book excerpt: Melanoma is one of the most types of cancer. When melanoma is detected at an early stage, treatment is highly successful, but outcomes can be poor when the disease is advanced. There has been significant progress in our understanding of the molecular biology, genetics, and immunology of melanoma over the past decade. This has been accompanied by rapid advances in therapeutic strategies for patients with melanoma. This book provides the clinician and the researcher with a broad understanding of the molecular and cellular pathogenesis of melanoma, explores the clinical characteristics and criteria for clinical and pathological staging of the disease, and provides an overview of current and evolving treatment strategies in the adjuvant, metastatic, and preventive settings. The treatment of special populations and rare variants of melanoma that often present particular clinical challenges is also covered. Authored by international experts in melanoma biology and clinical management, this volume concisely explains how to diagnose, treat, and prevent melanoma while reviewing advances in basic science and providing an overview of innovative approaches still under development.
Download or read book Advances in Prostate Cancer Model Systems Molecular and Cellular Mechanisms Early Detection and Therapies written by Tanya I. Stoyanova and published by Frontiers Media SA. This book was released on 2022-08-08 with total page 232 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Overcoming Dendritic Cell mediated Suppression of T Cell Responses in a Prostate Tumor Environment written by Eileen M. Higham and published by . This book was released on 2010 with total page 184 pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate cancer is the most prevalent malignancy in American men, leading to significant mortality each year. This is in part due to a lack of effective treatments for advanced disease. The prostate is considered an ideal organ for cancer immunotherapy, because it is both nonessential and expresses several prostate-specific antigens than could be targeted for an immuno- therapeutic response. However, such therapy is limited by the tolerization of CD8 T cells in tumors, rapidly abrogating anti-tumor responses. In order to better understand the factors necessary to induce, maintain and promote productive T cell responses against cancer, this research has focused on understanding and interrupting critical interactions between CD8+ T cells and immunosuppressive networks within tumors. As our model system, we explored CD8+ T cell recognition of spontaneous prostate cancer in TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. We demonstrated that both naive and effector tumor-reactive T cells are rapidly tolerized in the prostates and prostate draining lymph nodes (PDLN) of TRAMP mice, and that dendritic cells are important factors driving their tolerization. We then developed two novel immuno- therapeutic approaches to locally overcome the suppressive influence of dendritic cells. In one approach, we engineered tumor-reactive T cells to express the immunostimulatory protein CD40 ligand to mature dendritic cells in the PDLN. This work demonstrated for the first time that tumor-reactive T cells could be engineered to deliver stimulatory signals to dendritic cells in tumor environments to enhance the function of adoptively transferred T cells. In a second approach, we injected ex vivo matured, antigen-loaded dendritic cells into tumors to overcome the influence of endogenous suppressive dendritic cells. This work demonstrated for the first time that intratumoral injections of dendritic cells into spontaneous primary tumors could significantly delay the tolerization of tumor-infiltrating effector T cells and reverse the tolerization of resident tumor-infiltrating lymphocytes (TILs), generating new potential therapeutic applications for TILs. These two approaches establish that mechanism-based immuno- therapeutic interventions can be rationally designed to locally interrupt immunosuppressive networks within tumors. As the TILs enhanced through this work are representative of those found in cancer patients, such approaches could have significant clinical impact.
Download or read book Analysis of T Cell Responses During Anti PD 1 Anti CTLA 4 Dual Blockade Therapy and Anti PD 1 Monotherapy in Stage III IV Metastatic Melanoma Patients written by Zhen Zhang and published by . This book was released on 2024 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Combinational Immunotherapy of Cancer Novel Targets Mechanisms and Strategies written by Xuyao Zhang and published by Frontiers Media SA. This book was released on 2024-01-15 with total page 537 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer immunotherapy, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy, has revolutionized the paradigm in cancer treatment. However, the clinical outcome of immunotherapy varies considerably among patients and only a minority of patients achieve long-term clinical benefits. This is largely attributed to the fact that existing cancer immunotherapies, which concentrate on several classical targets (CTAL-4, PD-1/PD-L1, etc.) and limited types of immune cell populations (T cells), are insufficient to cope with the complexity of highly heterogeneous tumor microenvironment (TME). This calls for more efforts to not only expand our toolbox for manipulating anticancer immunity but also diversify our combinational strategies. To this end, it is urgent to deeper our understanding of cancer immunotherapy by using both experimental and computational methodologies from multi-scale perspectives: 1) novel targets from either tumor cells or non-tumor cells within TME (e.g., tumor intrinsic resistance drivers, new immune checkpoints, neoantigens), 2) in-depth characterization of more immune cell populations (e.g., macrophages, Tregs, B cells) and their interactions and dynamics within TME, 3) landscape of actionable targets in patient populations for combination design. These efforts will open the avenue of rational design of combinational immunotherapies, allowing researchers and clinicians to design novel targeting therapeutics or to optimally orchestrate combinatory strategies aiming to surmount resistance mechanisms and improve clinical outcomes.
Download or read book T Cell Mediated Combination Immunotherapy written by Cary Francis Opel and published by . This book was released on 2016 with total page 139 pages. Available in PDF, EPUB and Kindle. Book excerpt: Immunotherapy is a broad treatment strategy that harnesses the immune system to fight off a particular condition or disease. Cancer immunotherapy is the specific application of agents designed to interact or stimulate the immune system to fight off tumors. Treatments as diverse as passive antibody therapy, cytokine support, and comprehensive adoptive T cell transfer make up the broad field of immunotherapeutics. Due to the naturally complex interactions inherent in the immune system, there are many options for therapeutic intervention, however, this same complexity makes it extremely difficult to optimize treatment strategies. Because of this, research into developing new immunotherapies, optimizing existing immunotherapies, and designing new combinations of immunotherapies is still critical in the fight against cancer. Although there have been ongoing successes of individual immunotherapies in the clinic, the complexity and interdependence of the immune system suggests that any single therapeutic intervention will be insufficient to reject established malignancies. Increased interest in applying combinations of immunotherapies in the clinic requires more thorough preclinical work to guide the designs of these studies. The work presented in this thesis focuses on developing combinations of immunotherapies to treat preclinical models of cancer, as well as studying the underlying mechanism of tumor control. T cells are potent mediators of cytotoxicity and when properly used in adoptive cell transfer (ACT) protocols, can be highly effective in the treatment of cancer. ACT consists of three steps: 1) harvesting and purifying T cells from the patient, 2) enriching or modifying the T cells to become tumor specific, and 3) reinfusing the T cells along with supporting therapies. Therapies given alongside ACT are often adjuvants designed to enhance T cell response. However, focusing therapies only on enhancing the activity of the transferred T cells may miss out on synergistic effects when other parts of the immune system are simultaneously engaged. To study the effect of adjuvant therapy on ACT, a preclinical murine model was analyzed. Large, established B16F10 tumors were controlled when pmel-1 T cells were given with a course of supportive MSA-IL2 cytokine therapy, however, no cures were observed. When a course of TA99 antibody therapy was added alongside ACT, a high rate of cures was observed. Flow cytometry of both circulating and tumor infiltrating pmel-1 cells showed massive expansion and activation. Additionally, tumor infiltration of neutrophils, NK cells, and DCs were greatly enhanced by adjuvant therapy. DCs in the tumor draining lymph nodes were largely unchanged by the therapies. Engagement of the humoral immune response was also observed in both treatment cases. Surprisingly, antibody therapy did not substantially alter any of the mechanistic observations made in this study, despite its critical role in achieving cures of tumors. While ACT is a highly effective therapy, its clinical applicability is hindered by the complexity of performing T cell transplants and manipulations. A more optimal solution would involve purely injectable treatments that could elicit the same level of tumor specific T cell response in conjunction with potent recruitment of the adaptive immune system against tumors. To achieve this, working in collaboration with the Irvine Lab, combinations of immunotherapy using up to four different components were tested to identify critical factors in the successful rejection of established tumors in preclinical models. The four components of tumor targeting antibody, cytokine support, checkpoint blockade, and cancer vaccine acted synergistically to reject tumors from B16F10, TC-1, and DD-Her2/neu cell lines. The cancer vaccine elicited large numbers of tumor-specific T cells, and acted as a replacement for ACT. By analyzing subset combinations of this full treatment, the roles of each therapeutic component were identified. CD8 T cells and cross-presenting DCs were critical to curing subcutaneous tumors. Cytokine therapy was indispensable for effective tumor control, promoted immune cell infiltration into the tumor, and led to an increase in DCs. In combination with the other therapies, vaccination against a tumor antigen elicited a strong immunological memory response that was able to reject subsequent tumor rechallenge, as well as promote antigen spreading to new epitopes. Successful combinations were demonstrated to be dependent on the recruitment of both the adaptive and innate branches of the immune system. Finally, the efficacy of this combination of treatments was demonstrated by controlling the growth of induced tumors in a BRaf/Pten model. Combination immunotherapy promises a future where synergistic treatments are specifically tailored to individual cancers leading to highly effective responses. However, determining the optimal combination of therapies, the complexity of dosing strategies, and the availability of targeted treatments are all barriers that must be overcome. The analysis presented here will make a significant contribution to the body of knowledge on immunotherapy as it has shown the importance of combining orthogonal immunotherapies in order to get durable cures to established tumors. These results will hopefully encourage combinations of orthogonally acting therapies based on T cells to achieve stronger clinical responses. By determining the necessary requirements for a strong, synergistic response to tumorous growths, more effective combination immunotherapy protocols may be designed in the future.
Download or read book Irreversible Electroporation in Clinical Practice written by Martijn R. Meijerink and published by Springer. This book was released on 2017-12-27 with total page 281 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides a comprehensive overview of the clinical use of irreversible electroporation (IRE) – better known by its commercial name, NanoKnife – which is one of the most exciting new needle-guided cancer treatments. The coverage includes the history of IRE, general technique, preclinical research, applications in clinical practice and early clinical results, and future perspectives. Contraindications, treatment planning, potential complications, follow-up imaging, and other practical aspects are fully discussed, with highlighting of useful tips and tricks. Through the delivery of short but highly intense electrical pulses, IRE results in tumor cell membrane permeabilization, causing cells to go into apoptosis. The minimally invasive nature of IRE, combined with the prospect of completely eradicating tumors while preserving delicate structures in the ablation zone, makes IRE the object of worldwide clinical research. This book will be of value for practitioners and trainees in interventional and diagnostic radiology, surgery, medical oncology, HPB and gastroenterology, urology, and radiation oncology.
Download or read book The Function of CTLA4 During the in Vivo Immune Response to Infectious Disease written by Velia Mitro and published by . This book was released on 2000 with total page 227 pages. Available in PDF, EPUB and Kindle. Book excerpt:
