Download or read book Activating an in Situ Vaccine Response and Propagating Anti tumor Immunity Using Radiotherapies written by Justin Charles Jagodinsky and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Radiation is a mainstay of cancer therapy with over half of all patients receiving radiation therapy at some point throughout their clinical course. Though once thought of as primarily a cytotoxic therapy, growing eloquent preclinical work has outlined the complex interplay between radiation therapy and activation of key immune signaling pathways and effector cell populations. Several groups have taken advantage of immunostimulatory effects of radiation to generate an in situ vaccination, converting a patient's own tumor into a nidus for enhanced antigen presentation to drive a systemic immune response against distant sites of disease. However, responses generated against distant sites (i.e. abscopal response) following radiation remain rare. The advent of immunotherapy, particularly immune checkpoint blockade, has enabled propagation of the local immune response generated by radiation with remarkable success in preclinical models. Despite robust preclinical success, clinical translation remains limited. This may be due in part to the observation that the multitude of immune signaling pathways influenced by radiation each have a unique dose range for optimal activation, with no one single dose being able to optimally modulate all pathways. One goal of this thesis work was to investigate whether radiation dose heterogeneity, both temporal as administered via slow decay of a targeted radionuclide (targeted radionuclide therapy, TRT), and spatial as delivered via high dose rate brachytherapy (BT), offered meaningful advantages over homogenous dose radiation delivered via external beam radiation (EBRT). Delivery of TRT via 90Y decay resulted in a similar magnitude of immune activation compared to EBRT but with a protracted time course. This finding paired with the potential for TRT to modulate all sites of disease given its systemic nature likely underscore the capacity for TRT to generate more robust anti-tumor immunity compared to EBRT in a model of systemic disease. Spatial dose heterogeneity delivered via BT resulted in spatial heterogeneity in gene expression and T cell infiltration within the tumor microenvironment. Compared to low, moderate, and high dose EBRT, BT enabled peak activation of several immune pathways whereas each EBRT dose only enabled one. This was further borne out upon single cell RNA sequencing analysis. Each EBRT dose enriched unique immune cell clusters within the tumor microenvironment, whereas each of these clusters was represented in BT treated tumors. Subsequently, BT generated more robust anti-tumor immunity compared to EBRT in both localized and systemic disease models. In complementary work investigating additional methods to enhance in situ vaccination, we demonstrated the capacity of the infectious disease vaccine adjuvant monophosphoryl lipid A (MPL) to augment the anti-tumor effect of combination EBRT and checkpoint blockade. We observed that local delivery of MPL generated production of endogenous anti-tumor antibodies which were required for treatment efficacy. Through genetic knockout models we identified that the anti-tumor effect was dependent on induction of Th1 CD4 T cells and resulted from direct macrophage-mediated tumor cell killing via FcÎđR recognition but interestingly, was independent of CD8 T cells. These results suggest that this combination therapy may be particularly useful in settings of low MHC-1 expression which is associated with resistance to checkpoint blockade. BT as a treatment modality lends itself well to combination with intratumoral agents, given that catheters are placed within the tumor to deliver the radiation. To that end, we designed, created, and validated a multipurpose BT catheter to enable combination BT and intratumoral injection. As we gain further insight into immunosuppressive mechanisms occurring within the tumor microenvironment, it is becoming increasingly clear that combination approaches to treatment will be required to circumvent diverse resistance mechanisms.

Download or read book Tumor Ablation written by Yona Keisari and published by Springer Science & Business Media. This book was released on 2012-08-15 with total page 161 pages. Available in PDF, EPUB and Kindle. Book excerpt: The growing knowledge on tumor-immune response interactions and on the tumor microenvironment did not translate so far into better control of cancer by anti-tumor vaccination. The percentage of patients who benefited from vaccination strategies is still too small to justify their general use. It is the aim of this book to present an alternative to the conventional approach of developing injected tumor vaccines to activate anti-tumor immunity, which will fight cancer. It is argued that in situ tumor ablation (destruction) that involves tumor antigen release; cross presentation and the release of danger associated molecular patterns (DAMPs) can make the tumor its own cellular vaccine. Tumor ablation methods using chemicals, radiation, photodynamic therapy, cryoablation, high-temperature, radiofrequency, high intensity focused ultrasound, and electric-based ablation have been developed for focal tumors. In this book experts will deal with two main topics: I. What are the principles of the various ablation modalities, and II. How each method affects the tumor cells and their microenvironment, and how these effects are responsible for the induction of specific anti-tumor immunity. The aims of this book are thus: 1. Familiarize the readers with various methods of in situ tumor ablation. 2. Review the literature and stimulate comparisons on the efficacy of different ablation methods for the treatment of tumors of different histotypes. 3. Review the literature on the effects of various ablation methods on systemic and local anti tumor immunity and on other manifestations of the interactions of tumors with their microenvironment. 4. Stimulate comparative studies on the immunostimulatory effects of different ablation modalities.

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 Enhancing the Systemic Anti tumor Efficacy of in situ Vaccines Against Advanced Tumors written by Alexander Anthony Pieper and published by . This book was released on 2021 with total page 182 pages. Available in PDF, EPUB and Kindle. Book excerpt: Despite advancements in our ability to diagnosis and treat cancer, cancer progression still occurs in many patients. Disease progression at sites other than the treated tumor remains an obstacle for improved patient outcomes. In-situ cancer vaccine strategies use immunotherapeutics to increase antigen processing and adaptive cell priming at one site of disease, and their objective is to have this adaptive response mediate tumor cell killing at the local, treated tumor and at distant, untreated sites of disease. The Sondel lab has developed an effective in-situ vaccine strategy that combines local external beam radiation therapy (RT) with intratumoral injections of immunocytokine, which is a fusion protein comprised of interleukin 2 (IL-2) attached to a monoclonal antibody. In the weakly immunogenic B78 melanoma model, this in-situ vaccine can cure mice of established tumors and generate an adaptive, tumor-specific memory response. If the B78 model is made more difficult to treat by adding a second untreated tumor to the model or allowing the tumors to grow larger in size before treatment, RT combined with immunocytokine demonstrates reduced anti-tumor efficacy. The goal of this thesis was to explore mechanisms to improve our in-situ vaccination strategies, with a particular emphasis geared towards improving the strength of in-situ vaccines under model conditions that are deemed "hard-to-treat." Research with a different in-situ vaccine, local injections of CpG oligodeoxynucleotide combined with an OX40 agonist antibody (CpG+OX40), has shown the combination synergizes to cure mice bearing multiple A20 lymphoma tumors. In these studies, however, the tumors were relatively small at the time treatment was initiated. Additionally, the A20 lymphoma model is considered relatively immunogenic. By evaluating the efficacy of this in-situ vaccine in both the B78 and A20 models, these studies demonstrate CpG+OX40 is an effective in-situ vaccination strategy against relatively small tumors. However, as tumor burden increases through the addition of a second untreated tumor or allowing tumors to grow larger before treatment is initiated, these studies show the efficacy of CpG+OX40 is reduced. In the A20 model, there are tumor phenotypic changes that develop in these larger tumors, which correlate with the reduced efficacy of this T cell dependent in-situ vaccine against larger tumors. Radiation therapy (RT) has been studied for its ability to turn a weakly immunogenic tumor into one that is more immunogenic. The Sondel and Morris labs have utilized these immune modulating capabilities in their research, demonstrating that local radiation can make a weakly immunogenic tumor more responsive to immunotherapy. Chapter 3 of this dissertation presents data demonstrating that local radiation prior to in-situ vaccination with CpG+OX40 can render a tumor, which was previously unlikely to respond to immunotherapy, more likely to shrink and go away. The data suggest RT is functioning to improve the anti-tumor response with CpG+OX40 by increasing antigen presentation and T cell activation. Though the in-situ vaccine regimen RT+CpG+OX40 can cure some mice of established B78 tumors, the cure rate of this regimen was reduced compared to the historical data of combining RT with immunocytokine. In an effort to improve the efficacy of our in-situ vaccine strategies, studies were performed investigating if RT could be combined with a different immunotherapeutic, a novel IL-2 receptor agonist Bempegaldesleukin, to activate a strong T cell mediated anti-tumor immune response. This combination, RT combined with Bempegaldesleukin, was capable of curing mice of B78 tumors that have historically been less responsive to RT combined with immunocytokine. Additionally, these studies demonstrated that addition of checkpoint blockade to this combination of RT with Bempegaldesleukin can further enhance the anti-tumor response in model conditions that more closely mimic the disease characteristics in patients. The preclinical laboratory development of this in-situ vaccine regimen, RT combined with Bempegaldesleukin and checkpoint blockade, contributed to the design and initiation of a clinical trial that is now opening to accrual.

Download or read book Tumor Ablation written by Yona Keisari and published by Springer. This book was released on 2012-08-10 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The growing knowledge on tumor-immune response interactions and on the tumor microenvironment did not translate so far into better control of cancer by anti-tumor vaccination. The percentage of patients who benefited from vaccination strategies is still too small to justify their general use. It is the aim of this book to present an alternative to the conventional approach of developing injected tumor vaccines to activate anti-tumor immunity, which will fight cancer. It is argued that in situ tumor ablation (destruction) that involves tumor antigen release; cross presentation and the release of danger associated molecular patterns (DAMPs) can make the tumor its own cellular vaccine. Tumor ablation methods using chemicals, radiation, photodynamic therapy, cryoablation, high-temperature, radiofrequency, high intensity focused ultrasound, and electric-based ablation have been developed for focal tumors. In this book experts will deal with two main topics: I. What are the principles of the various ablation modalities, and II. How each method affects the tumor cells and their microenvironment, and how these effects are responsible for the induction of specific anti-tumor immunity. The aims of this book are thus: 1. Familiarize the readers with various methods of in situ tumor ablation. 2. Review the literature and stimulate comparisons on the efficacy of different ablation methods for the treatment of tumors of different histotypes. 3. Review the literature on the effects of various ablation methods on systemic and local anti tumor immunity and on other manifestations of the interactions of tumors with their microenvironment. 4. Stimulate comparative studies on the immunostimulatory effects of different ablation modalities.

Download or read book Using Low dose Radiation Therapy to Propagate Systemic Response to in Situ Vaccines written by Peter Michael Carlson and published by . This book was released on 2020 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Despite substantial improvement in clinical cancer care, disease progression still occurs. The Sondel lab has developed a combination in situ vaccine (ISV) immunotherapy approach consisting of 12Gy local external beam radiation (RT) and intratumoral injections of hu14.18-IL2 immunocytokine (IC, a fusion of an anti-GD2 monoclonal antibody and IL-2) for treatment of GD2+ tumors. This ISV approach can render up to 70% of mice bearing a single B78 melanoma flank tumor disease-free, with tumor-specific systemic memory, but is insufficient to control distant, untreated tumors in models of multiple B78 implanted tumors. The goal of this thesis was to characterize the efficacy of using low-dose radiation (both RT and molecular targeted radionuclide therapy [TRT, [90]Y-NM600]) delivered to all sites of disease in enabling a systemic antitumor response following RT/IC ISV. Many shared resource cytometry facilities do not permit analysis of radioactive tissue for safety and radioactive waste disposal concerns. By investigating introduction of a cryopreservation step in the flow cytometry workflow, I demonstrated that cryopreservation of dissociated tumor and spleen cells after all staining and fixation gave results most concordant with non-cryopreserved cells, which allowed for analyses of radioactive TRT-treated tumors. In addition, I characterized a discrepancy in treatment outcome among mice implanted with B78 tumors treated with ISV. I determined that tumors implanted subcutaneously display a 'fixed' phenotype and are less likely to respond to RT/IC ISV. Conversely, tumors implanted intradermally are 'mobile' in phenotype and respond well to RT/IC ISV. After controlling for implantation depth, I determined that RT/IC ISV delivered to a primary B78 melanoma combined with either RT or [90]Y-NM600 TRT to secondary tumors resulted in greater antitumor effect compared to either RT/IC alone or radiation alone, as demonstrated by overall survival, and analysis of tumor growth rates. These data suggest that additional radiation to all disease sites is indeed capable of improving response to RT/IC ISV at distant sites. Ongoing studies are using flow cytometry and cytokine quantification to characterize the nature of the immune response to ISV at distant tumors, with and without additional radiation.

Download or read book Priming Systemic Anti tumor Immunity Via in Situ Immunomodulation of the Tumor Microenvironment written by Lauren Elizabeth Milling and published by . This book was released on 2021 with total page 129 pages. Available in PDF, EPUB and Kindle. Book excerpt: Taking a more personalized vaccine approach, we secondly demonstrate that in vitro treatment of tumor cells with DNA-damaging chemotherapy can promote tumor antigen-specific T cell activation by dendritic cells. Intratumoral injection of these chemotherapy-damaged cells synergizes with immune checkpoint blockade to promote tumor regression. Together, these studies underscore the versatility of intratumoral immunomodulation and highlight the wholistic activation of both innate and adaptive immune cells, hopefully contributing to more patients benefiting from cancer immunotherapy.

Download or read book Oncoimmunology written by Laurence Zitvogel and published by Springer. This book was released on 2017-12-13 with total page 700 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book Cancer Vaccines and Immunotherapy written by Peter L. Stern and published by Cambridge University Press. This book was released on 2000-08-17 with total page 304 pages. Available in PDF, EPUB and Kindle. Book excerpt: Rapid progress in the definition of tumor antigens, and improved immunization methods, bring effective cancer vaccines within reach. In this wide-ranging survey, leading clinicians and scientists review therapeutic cancer vaccine strategies against a variety of diseases and molecular targets. Intended for an interdisciplinary readership, their contributions cover the rationale, development, and implementation of vaccines in human cancer treatment, with specific reference to cancer of the cervix, breast, colon, bladder, and prostate, and to melanoma and lymphoma. They review target identification, delivery vectors and clinical trial design. The book begins and ends with lucid overviews from the editors, that discuss the most recent developments.

Download or read book Peptide and Protein Vaccines written by Rossen Donev and published by Academic Press. This book was released on 2015-06-08 with total page 192 pages. Available in PDF, EPUB and Kindle. Book excerpt: Published continuously since 1944, the Advances in Protein Chemistry and Structural Biology series has been the essential resource for protein chemists. Each volume brings forth new information about protocols and analysis of proteins. Each thematically organized volume is guest edited by leading experts in a broad range of protein-related topics. Describes advances in application of powerful techniques in a wide bioscience area Chapters are written by authorities in their field Targeted to a wide audience of researchers, specialists, and students The information provided in the volume is well supported by a number of high quality illustrations, figures, and tables

Download or read book Nanomedicine for Cancer Therapy written by Piyush Kumar and published by Springer. This book was released on 2016-11-21 with total page 77 pages. Available in PDF, EPUB and Kindle. Book excerpt: This Brief focuses on the cancer therapy available till date, from conventional drug delivery to nanomedicine in clinical trial. In addition, it reports on future generation based nanotherapeutics and cancer theranostic agent for effective therapeutic diagnosis and treatment. Breast cancer was chosen as the model system in this review. The authors give emphasis to multiple drug resistance (MDR) and its mechanism and how to overcome it using the nanoparticle approach.

Download or read book Immunotherapy of Hepatocellular Carcinoma written by Tim F. Greten and published by Springer. This book was released on 2018-08-22 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: In this book we provide insights into liver – cancer and immunology. Experts in the field provide an overview over fundamental immunological questions in liver cancer and tumorimmunology, which form the base for immune based approaches in HCC, which gain increasing interest in the community due to first promising results obtained in early clinical trials. Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death in the United States. Treatment options are limited. Viral hepatitis is one of the major risk factors for HCC, which represents a typical “inflammation-induced” cancer. Immune-based treatment approaches have revolutionized oncology in recent years. Various treatment strategies have received FDA approval including dendritic cell vaccination, for prostate cancer as well as immune checkpoint inhibition targeting the CTLA4 or the PD1/PDL1 axis in melanoma, lung, and kidney cancer. Additionally, cell based therapies (adoptive T cell therapy, CAR T cells and TCR transduced T cells) have demonstrated significant efficacy in patients with B cell malignancies and melanoma. Immune checkpoint inhibitors in particular have generated enormous excitement across the entire field of oncology, providing a significant benefit to a minority of patients.

Download or read book Immunopotentiators in Modern Vaccines written by Virgil Schijns and published by Elsevier. This book was released on 2005-12-19 with total page 396 pages. Available in PDF, EPUB and Kindle. Book excerpt: Immunopotentiators in Modern Vaccines provides an in-depth insight and overview of a number of most promising immunopotentiators in modern vaccines. In contrast to existing books on the subject it provides recent data on the critical mechanisms governing the activity of vaccine adjuvants and delivery systems. Knowledge of immunological pathways and scenarios of the cells and molecules involved is described and depicted in comprehensive illustrations. Contributions from leading international authorities in the field Well-illustrated, informative figures present the interactions between immunopotentiators and the host immune system Each chapter lists advantages and potential hurdles for achieving a practical application for the specific immunopentiator

Download or read book Inflammation and Cancer written by Bharat B. Aggarwal and published by Springer. This book was released on 2014-05-12 with total page 489 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume examines in detail the role of chronic inflammatory processes in the development of several types of cancer. Leading experts describe the latest results of molecular and cellular research on infection, cancer-related inflammation and tumorigenesis. Further, the clinical significance of these findings in preventing cancer progression and approaches to treating the diseases are discussed. Individual chapters cover cancer of the lung, colon, breast, brain, head and neck, pancreas, prostate, bladder, kidney, liver, cervix and skin as well as gastric cancer, sarcoma, lymphoma, leukemia and multiple myeloma.

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 Innovations for Next Generation Antibody Drug Conjugates written by Marc Damelin and published by Springer. This book was released on 2018-05-29 with total page 358 pages. Available in PDF, EPUB and Kindle. Book excerpt: Antibody-drug conjugates (ADCs) stand at the verge of a transformation. Scores of clinical programs have yielded only a few regulatory approvals, but a wave of technological innovation now empowers us to overcome past technical challenges. This volume focuses on the next generation of ADCs and the innovations that will enable them. The book inspires the future by integrating the field’s history with novel strategies and cutting-edge technologies. While the book primarily addresses ADCs for solid tumors, the last chapter explores the emerging interest in using ADCs to treat other diseases. The therapeutic rationale of ADCs is strong: to direct small molecules to the desired site of action (and away from normal tissues) by conjugation to antibodies or other targeting moieties. However, the combination of small and large molecules imposes deep complexity to lead optimization, pharmacokinetics, toxicology, analytics and manufacturing. The field has made significant advances in all of these areas by improving target selection, ADC design, manufacturing methods and clinical strategies. These innovations will inspire and educate scientists who are designing next-generation ADCs with the potential to transform the lives of patients.

Download or read book Immunotherapy written by Aung Naing and published by Springer Nature. This book was released on 2022-01-01 with total page 445 pages. Available in PDF, EPUB and Kindle. Book excerpt: The field of immuno-oncology continues to rapidly evolve as new insights to fight and treat cancer emerge. The fourth edition of Immunotherapy provides the most current overview of immuno-oncology in different cancer types and toxicities associated with immunotherapy. While immunotherapy has revolutionized the treatment landscape of several solid malignancies, several challenges still exist. Only a subset of patients derive clinical benefits; some do not respond at all, and others respond initially, only for their disease to progress later. Because these drugs can activate a broad range of immune cells, patients suffer from a unique set of side effects known as immune-related adverse events. As more immunotherapeutic agents are used in the clinic, it is important to provide updates about current and ongoing developments in the field to further research efforts and inform treatment decisions. The fourth edition will have a new focus on strategies to overcome the challenges associated with immunotherapy. Chapters will discuss topics such as biomarkers of response, resistance mechanisms, role of imaging in predicting immune-related adverse events, and management of immune-related adverse events. Written by leading experts conducting cutting-edge research, readers will gain up-to-date knowledge on the current state and future of immunotherapy.