Immunotherapy of Diffuse Gliomas: Biological Background, Current Status and Future Developments

Despite aggressive multimodal treatment approaches, the prognosis for patients with diffuse gliomas remains disappointing. Glioma cells often extensively infiltrate in the surrounding brain parenchyma, a phenomenon that helps them to escape surgical removal, radiation exposure and chemotherapy. Moreover, conventional therapy is often associated with considerable local and systemic side effects. Therefore, the development of novel therapeutic approaches is essential to improve the outcome of these patients. Immunotherapy offers the opportunity to specifically target residual radio—and chemoresistant tumor cells without damaging healthy neighboring brain tissue. Significant progress has been made in recent years both in understanding the mechanisms of immune regulation in the central nervous system (CNS) as well as tumor-induced and host-mediated immunosuppression elicited by gliomas. In this review, after discussing the special requirements needed for the initiation and control of immune responses in the CNS, we focus on immunological phenomena observed in glioma patients, discuss different immunological approaches to attack glioma-associated target structures and touch on further strategies to improve the efficacy of immunotherapy of gliomas.     

磁性纳米颗粒的产热机制及在肿瘤热疗中的应用

磁热疗是继放射治疗、化学药物治疗后新兴的一种微创肿瘤治疗手段。磁性纳米颗粒在外加磁场下靶向病变部位并积集于此,在交变磁场中磁滞或弛豫产热,使病变部位快速升温。磁热在肿瘤微环境使其发生蛋白质变性、DNA损伤、免疫系统激活等,可在短时间内安全有效地杀死肿瘤细胞。综述磁性纳米颗粒的产热机制,在肿瘤磁热疗中与细胞的相互作用,及与其他肿瘤治疗方式的协同作用,并讨论其对细胞毒性和治疗的副作用。     

Combining targeted therapy with immunotherapy. Can 1 + 1 equal more than 2?

Targeted therapies have induced high response rates and improved survival in patients with cancer. However, the long-term effectiveness of targeted therapies has been limited by the development of acquired resistance in the majority of patients. On the other hand, the modern immunotherapy strategies have been associated with durable responses but in limited number of patients. Accordingly, research efforts have been focused on examining the effects of combinations of targeted therapy and immunotherapy in several different histological subtypes of cancer. There has been accumulated evidence to suggest that targeted therapy can induce immune effects in the tumor cells, the host immune system, and the tumor microenvironment. Subsequently, clinical trials have been designed to examine the efficacy of combining immune checkpoint blockade or adoptive cell transfer with tyrosine kinase inhibitors, HER family blockade, anti-angiogenic agents, histone deacetylase inhibitors, and cancer stem cell inhibitors. To date, the combination of immunotherapy with targeted therapy has demonstrated potential as a cancer treatment strategy, but further optimizations are required and caution must be taken to avoid toxicity. The current review summarizes existing evidence and provides rationale supporting the use of combined targeted and immune-therapy approaches in patients with different types of cancer.     

CAR T cells for brain tumors: Lessons learned and road ahead

Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.     

Autophagy inhibition in cancer therapy: metabolic considerations for antitumor immunity

Summary: Tumors and the immune system are intertwined in a competition where tilting the fine balance between tumor-specific immunity and tolerance can ultimately decide the fate of the host. Defensive and suppressive immunological responses to cancer are exquisitely sensitive to metabolic features of rapidly growing tumors, such as hypoxia, low nutrient availability, and aberrant growth factor signaling. As a result, clinical therapies impacting these properties change the in situ antitumor immune response by virtue of disrupting the tumor environment. To compensate for disruptions in cellular metabolism, cells activate autophagy to promote survival. On the basis of this notion, strategies designed to block autophagy in tumor cells are currently being tested in several human clinical trials. However, therapies that impair tumor metabolism must also take into account their effect on lymphocytes activated in the immune response to cancer. Given that a strong antitumor immune response is a positive prognostic factor in overall patient survival, identifying ways to block essential processes in tumor cells and suppressive immune cells while promoting those that are important for a robust immune response are of critical importance. Herein, we review the effects of anti-cancer agents that impact metabolism administered concurrently with autophagy inhibitors on immune cells and consider the implications for patient response to therapy.     

Systems level immune response analysis and personalized medicine

The immune system is an anatomically structured, orchestrated interaction of different cell types that communicate via a large number of receptors recognizing both soluble and cellular ligands. Recent technological advances now allow large-scale measurements for better appreciation of this complexity. Despite these advances, only a few immunological parameters are routinely measured in clinical practice. The authors believe that these measurements are insufficient to describe the immune function of individual patients and thus cannot be used to evaluate immune-mediated diseases or response to therapy. Our current knowledge of immunology comes largely from work in murine model systems where the immune system has been characterized in great detail. This impressive volume of knowledge has proven to be difficult to translate into novel therapies in humans; one reason for this is the lack of large-scale immune monitoring allowing for systems-wide analysis of the human immune system. The authors propose a systems approach to immunology, where the focus is moved from analysis of individual cell types towards more integrated studies of the entire immune system. Exercising ‘systems immunology’ in preclinical research, during drug development and in patients undergoing therapies affecting the immune system, will enable us to improve clinical results through personalized medicine and help to define clinically relevant patterns of immune reactivity.     

Natural killer (NK):dendritic cell (DC) cross talk induced by therapeutic monoclonal antibody triggers tumor antigen-specific T cell immunity

Tumor antigen (TA)-targeted monoclonal antibodies (mAb), trastuzumab, cetuximab, panitumumab, and rituximab, have been among the most successful new therapies in the present generation. Clinical activity is observed as a single agent, or in combination with radiotherapy or chemotherapy, against metastatic colorectal cancer, head and neck cancer, breast cancer, and follicular lymphoma. However, the activity is seen only in a minority of patients. Thus, an intense need exists to define the mechanism of action of these immunoactive mAb. Here, we discuss some of the likely immunological events that occur in treated patients: antibody-dependent cellular cytotoxicity (ADCC), cross talk among immune cells including NK cells and dendritic cells (DCs), and generation of TA-specific T lymphocyte responses. We present evidence supporting the induction of "NK:DC cross talk," leading to priming of TA-specific cellular immunity. These observations show that mAb-mediated NK cell activation can be greatly enhanced by the action of stimulatory cytokines and surface molecules on maturing DC and that NK:DC interaction facilitates the recruitment of both NK cells and DC to the tumor site(s). The cooperative, reciprocal stimulatory activity of both NK cells and DC can modulate both the innate immune response in the local tumor microenvironment and the adaptive immune response in secondary lymphoid organs. These events likely contribute to clinical activity, as well as provide a potential biomarker of response to mAb therapy.     

Molecular pathogenesis. Its importance in targeted therapy in colorectal cancer

Colorectal cancer has the second highest mortality of all cancers in Germany. In spite of advances in surgical and chemotherapeutic treatment, efficient new therapies need to be developed. In recent years, advances have been achieved by novel targeted therapies that are specifically directed against altered signaling pathways of malignant cells. Colorectal cancers represent a heterogeneous tumor entity, and response to targeted therapies varies individually. About 15% of colorectal carcinomas are characterized by a deficient DNA mismatch repair system and microsatellite instability (MSI). These MSI cancers apparently have a decreased sensitivity to chemotherapy and frequently show evidence of a pronounced anti-tumoral immune response of the host. This immune response is likely to be mediated by a high number of tumor-specific antigens generated during MSI tumorigenesis. Interventions specifically targeting these antigens may be the basis for novel therapeutic strategies in MSI colorectal cancer and will be evaluated in clinical trials.     

Research advances on targeted-Treg therapies on immune-mediated kidney diseases

The primary function of regulatory T cells (Tregs) is blocking the pathogenic immunological response mediated by autoreactive cells, establishing and maintaining immune homeostasis in tissues. Kidney diseases are often caused by Immune imbalance, including alloimmune graft damage after renal transplantation, direct immune-mediated kidney diseases like membranous nephropathy (MN) and anti-glomerular basement membrane (anti-GBM) glomerulonephritis, as well as indirect immune-mediated ones like Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAVs), IgA nephropathy (IgAN) and lupus nephritis (LN). Treg cells are deficient numerically and/or functionally in those kidney diseases. Targeted-Treg therapies, including adoptive Tregs transfer therapy and low-dose IL-2 therapy, have begun to thrive in treating autoimmune diseases in recent years. However, the clinical use of targeted Treg-therapies is rarely mentioned in those kidney diseases above except for kidney transplantation. This article mainly discusses the newest progressions of targeted-Treg therapies in those specific examples of immune-mediated kidney diseases. Meanwhile, we also reviewed the main factors that affect Treg development and differentiation, hoping to inspire new strategies to develop target Tregs-therapies. Lastly, we emphasize the significant impediments and prospects to the clinical translation of target-Treg therapy. We advocate for more preclinical and clinical studies on target Tregs-therapies to decipher Tregs in those diseases.     

Targeted cancer therapy – Are the days of systemic chemotherapy numbered?

Targeted therapy or molecular targeted therapy has been defined as a type of treatment that blocks the growth of cancer cells by interfering with specific cell molecules required for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells as with traditional chemotherapy. There is a growing number of FDA approved monoclonal antibodies and small molecules targeting specific types of cancer suggestive of the growing relevance of this therapeutic approach. Targeted cancer therapies, also referred to as “Personalized Medicine”, are being studied for use alone, in combination with other targeted therapies, and in combination with chemotherapy. The objective of personalized medicine is the identification of patients that would benefit from a specific treatment based on the expression of molecular markers. Examples of this approach include bevacizumab and olaparib, which have been designated as promising targeted therapies for ovarian cancer. Combinations of trastuzumab with pertuzumab, or T-DM1 and mTOR inhibitors added to an aromatase inhibitor are new therapeutic strategies for breast cancer. Although this approach has been seen as a major step in the expansion of personalized medicine, it has substantial limitations including its high cost and the presence of serious adverse effects. The Cancer Genome Atlas is a useful resource to identify novel and more effective targets, which may help to overcome the present limitations. In this review we will discuss the clinical outcome of some of these new therapies with a focus on ovarian and breast cancer. We will also discuss novel concepts in targeted therapy, the target of cancer stem cells.     

Immune checkpoint inhibitors in cancer therapy

In recent years immune checkpoint inhibitors have garnered attention as being one of the most promising types of immunotherapy on the horizon. There has been particular focus on the immune checkpoint molecules, cytotoxic Tlymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) which have been shown to have potent immunomodulatory effects through their function as negative regulators of T cell activation. CTLA-4, through engagement with its ligands B7-1 (CD80) and B7-2 (CD86), plays a pivotal role in attenuating the activation of na?ve and memory T cells. In contrast, PD-1 is primarily involved in modulating T cell activity in peripheral tissues via its interaction with PD-L1 and PD-L2. The discovery of these negative regulators of the immune response was crucial in the development of checkpoint inhibitors. This shifted the focus from developing therapies that targeted activation of the host immune system against cancer to checkpoint inhibitors, which aimed to mediate tumor cell destruction through the removal of coinhibitory signals blocking anti tumor T cell responses.     

Incomplete tumor volume reduction may improve cancer prognosis

Currently, chemotherapy, immunotherapy, and radiotherapy are the standard treatment for un-resectable solid malignant tumors. New "virtual scalpel" methods, such as MRI guided focused ultrasound, can target tumor tissues for destruction without the need for a resection and its possible complications. Unfortunately, the current state of the art cannot guarantee the safe and full destruction of all the targeted tissues. The main hypothesis is that for cancer patients, even incomplete tumor volume reduction will increase the efficiency of some systemic therapies as well as of natural healing mechanisms, and thus, may improve the quality of life and the prognosis. It is conjectured that partial tumor volume destruction will reduce the releases of endocrine substances from tumor cells, thus, improving the overall systemic condition. Furthermore, it may improve the efficiency of chemotherapy and immunotherapy and possibly trigger a natural immune response. The decrease of tumor volume may also slow down the process of invasion and metastasis. It is recommended that as a standard practice of palliative care, any un-resectable tumor volume will be considered for destruction with virtual scalpel techniques such as MRI guided focused ultrasound. Furthermore, it is suggested that this process is synergetic with chemotherapy and immunotherapy.     

Clinical trials of vaccines for immunotherapy in pancreatic cancer

A greater understanding of the molecular events that trigger oncogenesis and events that negatively regulate immune responses has allowed for the development of targeted therapies with specific vaccines to match tumor antigens coupled with immunotherapy specifically directed against that tumor's immunosuppressive microenvironment. In order to be effective, vaccine therapies need to both expand the immune response to tumors and overcome immunosuppressive microenvironments therein. Specifically, targeted therapy must be personalized for each cancer patient. While the idea of personalized targeted therapy may seem like a daunting task, it may not be that difficult as it could involve a relatively simple genetic test to identify gene mutations and additional immunohistochemical staining of tumors with antibodies directed against markers of negative immune regulation. The additional cost to personalize cancer therapy with these diagnostic tests is relatively small in comparison to the cost afforded to our healthcare system when inappropriate targeting therapies are administered to patients whose tumors do not express the targets of either the vaccine or the immune modulator. Despite the large cost, cancer patients whose tumors lack the targets of these therapies often receive no benefit from the therapy. The most illogical approach is to develop a study design and perform clinical trials of potential novel targeting drugs without knowledge or confirmation that the patients' tumors express the targets. Current cancer trials for pancreatic cancer patients are discussed in this article.     

Immunological considerations of modern animal models of malignant primary brain tumors

Recent advances in animal models of glioma have facilitated a better understanding of biological mechanisms underlying gliomagenesis and glioma progression. The limitations of existing therapy, including surgery, chemotherapy, and radiotherapy, have prompted numerous investigators to search for new therapeutic approaches to improve quantity and quality of survival from these aggressive lesions. One of these approaches involves triggering a tumor specific immune response. However, a difficulty in this approach is the the scarcity of animal models of primary CNS neoplasms which faithfully recapitulate these tumors and their interaction with the host's immune system. In this article, we review the existing methods utilized to date for modeling gliomas in rodents, with a focus on the known as well as potential immunological aspects of these models. As this review demonstrates, many of these models have inherent immune system limitations, and the impact of these limitations on studies on the influence of pre-clinical therapeutics testing warrants further attention.     

PERIPHERAL TOLERANCE TO ALLOANTIGEN: STRATEGIES FOR THE FUTURE

The mature, adult immune system is specifically designed to eliminate any foreign material that may enter the body, but not to respond to the body's own tissues and molecules. Indeed, during development, the potential of the immune system to respond to self antigens is removed, by eliminating or effectively silencing any autoreactive cells. These features are well adapted under normal circumstances, as they result in the efficient elimination of potentially harmful agents thereby protecting the body from infection and malignancy. However, in the context of transplantation, this ‘normal’ response is diametrically opposed to the desired clinical outcome, which is clearly the long term function and survival of the transplanted tissue. To prevent graft rejection the immune system of the transplant recipient has to be manipulated to ensure that it is incapacitated. Immunosuppressive drugs can be used for this purpose and are undoubtedly effective; indeed they have had a dramatic impact on success rates in clinical organ transplantation. However, as the mechanism of action of these chemical immunosuppressants is immunologically non-specific, any immune response the recipient may need to make after transplantation, as well as the rejection response, is suppressed. In addition, to maintain graft survival the drugs have to be taken indefinitely after transplantation and therefore their use is not only associated with immunological complications such as increased risks of infection and malignancy, but also numerous non-immunological side-effects. One way to overcome these problems would be to develop strategies for specific immunosuppression, such that only leukocytes capable of responding to the foreign histocompatibility or alloantigens expressed by the transplanted tissue would be affected. The ability to manipulate or reprogramme the adult immune system in such a way as to induce specific immunological unresponsiveness or tolerance to the alloantigens of the organ donor would offer many advantages over conventional immunosuppressive therapy. Only leukocytes reactive with donor alloantigens would be affected, thus allowing transplant recipients to respond effectively to other immunological stimuli, such as virus infections.     

Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication

The continual interaction of the immune system with a developing tumor is thought to result in the establishment of a dynamic state of equilibrium. This equilibrium depends on the balance between effector and regulatory T-cell compartments. Whereas regulatory T cells can infiltrate and accumulate within tumors, effector T cells fail to efficiently do so. Furthermore, effector T cells that do infiltrate the tumor become tightly controlled by different regulatory cellular subsets and inhibitory molecules. The outcome of this balance is critical to survival, and whereas in some cases the equilibrium can rapidly result in the elimination of the transformed cells by the immune system, in many other cases the tumor manages to escape immune control. In this review, we discuss relevant work focusing on the establishment of the intratumor balance, the dynamic changes in the populations of effector and regulatory T cells within the tumor, and the role of the tumor vasculature and its activation state in the recruitment of different T-cell subsets. Finally, we also discuss work associated to the manipulation of the immune response to tumors and its impact on the infiltration, accumulation, and function of tumor-reactive lymphocytes within the tumor microenvironment.     

New insights into TB physiology suggest untapped therapeutic opportunities

The current regimens used to treat tuberculosis are largely comprised of serendipitously discovered drugs that are combined based on clinical experience. Despite curing millions, these drug regimens are limited by the long course of therapy, the emergence of resistance, and the persistent tissue damage that remains after treatment. The last two decades have produced only a single new drug but have represented a renaissance in our understanding of the physiology of tuberculosis infection. The advent of mycobacterial genetics, sophisticated immunological methods, and imaging technologies have transformed our understanding of bacterial physiology as well as the contribution of the host response to disease outcome. Specific alterations in bacterial metabolism, heterogeneity in bacterial state, and drug penetration all limit the effectiveness of antimicrobial therapy. This review summarizes these new biological insights and discusses strategies to exploit them for the rational development of more effective therapeutics. Three general strategies are discussed. First, our emerging insight into bacterial physiology suggests new pathways that might be targeted to accelerate therapy. Second, we explore whether the concept of genetic synergy can be used to design effective combination therapies. Finally, we outline possible approaches to modulate the host response to accentuate antibiotic efficacy. These biology-driven strategies promise to produce more effective therapies.     

Immunological weapons against acute myeloid leukaemia

A better understanding of the biology of malignant cells and of the host immune system together with dramatic advances in technology have led to the design of innovative immune-mediated approaches to control neoplastic clones, including various haematological malignancies. One of the major problems with conventional cancer therapies is their inability to eradicate residual cancer cells that are resistant to therapy, hence immune intervention might improve the clinical outcome of patients. This mini-review will focus mainly on immunological approaches to the therapy of acute myeloid leukaemia (AML), a subset of a much larger family of leukaemias. Immune-mediated approaches ranging from allogeneic lymphocyte transplants to cytokine therapy, immune-gene therapy and vaccination by dendritic-cell-based vaccines will be discussed.     

Lymphoid tissue reactions in rheumatoid arthritis

Frequently, the immune cell infiltrate of chronically inflamed tissues develops functional germinal centres and acquires structural features of secondary lymphoid organs. Ectopic lymphoid structures occur in peripheral tissues not only during autoimmune diseases but also in tumors (reactive infiltrate), chronic infections and graft rejection, indicating a strong link between lymphoid neogenesis and persistent antigen driven immune/inflammatory responses. There has been a renewed interest in ectopic lymphoid neogenesis, as better understanding of the mechanisms underpinning this process could contribute to elucidate the bio-pathological mechanisms involved in transition from acute-self resolving to chronic immunological aggression as well as identify novel therapeutic targets. Here we critically review recent clinical and biological studies addressing the role of ectopic lymphoid neogenesis specifically in rheumatoid arthritis.