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Species and Cell Types / Human / Immune System / Lymphocyte / Regulatory T Cell

New Approaches for the Immunotherapy of Acute Myeloid Leukemia

Abstract: Acute myeloid leukemia (AML) is a set of related diseases characterized by the immortalization and uncontrolled expansion of myeloid precursor cells. Core therapy for AML has remained unchanged for nearly 30 years, and survival rates remain unsatisfactory. However, advances in the immunotherapy of AML have created opportunities for improved outcomes. Enforcing a tumor-specific immune response through the re-direction of the adaptive immune system, which links remarkable specificity with potent cytotoxic effector functions, has proven particularly compelling. This may be coupled with immune checkpoint blockade and conventional therapies for optimal effect. Engineered antibodies are currently in use in AML and the repertoire of available therapeutics will expand. NK cells have shown effectiveness in this disease. New methods to optimize their activation and the targeting of AML show potential. Most significantly, adoptive immunotherapy with tumor-specific T cells, and particularly T cells re-directed using genetically introduced TCR or chimeric antigen receptors, have demonstrated promise. Each of these approaches has unique benefits and challenges that we explore in this review. ... Read more

Advances in Strategies and Methodologies in Cancer Immunotherapy

Abstract: Since the invention of Coley's toxin by William Coley in early 1900s, the path for cancer immunotherapy has been a convoluted one. Although still not considered standard of care, with the FDA approval of trastuzumab, Provenge and ipilimumab, the medical and scientific community has started to embrace the possibility that immunotherapy could be a new hope for cancer patients with otherwise untreatable metastatic diseases. This review aims to summarize the development of some major strategies in cancer immunotherapy, from the earliest peptide vaccine and transfer of tumor specific antibodies/T cells to the more recent dendritic cell (DC) vaccines, whole cell tumor vaccines, and checkpoint blockade therapy. Discussion of some major milestones and obstacles in the shaping of the field and the future perspectives is included. Photoimmunotherapy is also reviewed as an example of emerging new therapies combining phototherapy and immunotherapy. ... Read more

Wnt Signaling in Dendritic Cells: Its Role in Regulation of Immunity and Tolerance

Abstract: A fundamental puzzle in immunology is how the immune system launches robust immunity against pathogens while maintaining a state of tolerance to the body's own tissues and the trillions of commensal microorganisms and food antigens that confront them every day. Innate immune cells, such as dendritic cells (DCs) and macrophages, play a fundamental role in this process. Emerging studies have highlighted that the Wnt signaling pathway, particularly in DCs, plays a major role in regulating tolerance versus immunity. Here, we review our current understanding of how Wnt-signaling shapes the immune response and, in addition, highlight unanswered questions, the solution of which will be imperative in the rational exploitation of this pathway in vaccine design and immune therapy. ... Read more

Immune Effects of Targeted Radiation Therapy for Cancer

Abstract: Radiation therapy plays an important role in the treatment of the majority of cancers, and is commonly used to treat both localized and metastatic disease. Immunotherapy has recently been firmly integrated into the treatment of metastatic melanoma, and holds significant promise in treating a variety of other cancers. Although large field radiation has historically been appreciated for its immunosuppressive ability, targeted radiation can induce substantial changes in the tumor microenvironment beyond cellular cytotoxicity that evoke innate and adaptive immune responses. Previous studies have highlighted radiation-induced changes in proinflammatory cytokines, chemokines, effector, and immunosuppressive T cell subsets, as well as in immune receptors on tumor cells. Some of these changes in localized and systemic immune mediators have been linked to expansion of tumor-reactive T cells, improved clinical responses, and increased overall survival in preclinical and clinical models. Taken together, this evidence suggests that targeted radiation therapy can impact anti-tumor immune responses, and may potentially be combined with immunotherapy for synergistic effect. ... Read more

Why Is Coinfection with Influenza Virus and Bacteria So Difficult to Control?

Abstract: Influenza viruses are genetically labile pathogens which avoid immune detection by constantly changing their coat proteins. Most human infections are caused by mildly pathogenic viruses which rarely cause life-threatening disease in healthy people, but some individuals with a weakened immune system can experience severe complications. Widespread infections with highly pathogenic strains of influenza virus are less common, but have the potential to cause enormous death tolls among healthy adults if infection rates reach pandemic proportions. Increased virulence has been attributed to a variety of factors, including enhanced susceptibility to coinfection with common strains of bacteria. The mechanisms that facilitate dual infection are a major focus of current research, as preventative measures are needed to avert future pandemics. ... Read more

Immune Checkpoint Blockade as a Novel Immunotherapeutic Strategy for Renal Cell Carcinoma: A Review of Clinical Trials

Abstract: Renal cell carcinoma (RCC) is a common genitourinary malignancy; when metastatic, it is almost uniformly fatal. For many years non-specific immunotherapy was the mainstay of treatment for metastatic RCC, but led to only modest success and significant side-effects. More recently, seven targeted therapy drugs have been approved to treat metastatic RCC; these drugs impede RCC cell growth, proliferation, and angiogenesis and have had a significant impact on patient outcomes, but with infrequent long term responders. Thus, a renewed emphasis on immunotherapy has emerged over the last several years with the development and testing of a novel class of immunotherapeutic agents called checkpoint inhibitors. These drugs have targeted the programmed cell death 1 (PD-1) and cytotoxic leukocyte antigen 4 (CTLA-4) pathways on regulatory T cells, leading to immune response enhancement and immune-mediated anti-tumor effects in multiple malignancies, including RCC. A number of studies recently reported utilizing checkpoint inhibitors, either alone or in combination with other checkpoint inhibitors or vascular endothelial growth factor targeting agents, and these studies have shown significant and at times durable responses in RCC patients. This has led to the development of further phase I, II, and III trials and this review will discuss the history and currently available data for immune checkpoint blockade in RCC. ... Read more

MicroRNAs Regulate Immune System Via Multiple Targets

Abstract: MicroRNAs (miRNAs) represent the most abundant class of regulators of gene expression. Each miRNA may suppress multiple mRNA targets, while one mRNA can be targeted by many miRNAs for precise control of a wide range of cellular processes. The important role of miRNAs in the immune system is highlighted by the conditional Dicer knockout mouse, which exhibited profound aberrant development and function of immune cells. One particular miRNA, miR-155, is highly expressed and plays important role in lymphocytes. In this review we focused on the role of miRNA, especially miR-155, via their predicted and known mRNA targets in innate and adaptive immunity. Finally, we discussed the potential of miRNAs as novel targets for the diagnosis and therapy of immune system diseases. ... Read more

Mesenchymal Stem Cell-Based Therapy for Type 1 Diabetes

Abstract: Diabetes has increasingly become a worldwide health problem, causing huge burden on healthcare system and economy. Type 1 diabetes (T1D), traditionally termed "juvenile diabetes" because of an early onset age, is affecting 5~10% of total diabetic population. Insulin injection, the predominant treatment for T1D, is effective to ameliorate the hyperglycemia but incompetent to relieve the autoimmunity and to regenerate lost islets. Islet transplantation, an experimental treatment for T1D, also suffers from limited supply of human islets and poor immunosuppression. The recent progress in regenerative medicine, especially stem cell therapy, has suggested several novel and potential cures for T1D. Mesenchymal stem cell (MSC) based cell therapy is among one of them. MSCs are a type of adult stem cells residing in bone marrow, adipose tissue, umbilical cord blood, and many other tissues. MSCs, with self-renewal potential and transdifferentiation capability, can be expanded in vitro and directed to various cell lineages with relatively less efforts. MSCs have well-characterized hypoimmunogenicity and immunomodulatory effect. All these features make MSCs attractive for treating T1D. Here, we review the properties of MSCs and some of the recent progress using MSCs as a new therapeutic in the treatment of T1D. We also discuss the strength and limitations of using MSC therapy in human trials. ... Read more

Tolerance Induction in Hemophilia A Animal Models: Battling Inhibitors with Antigen-specific Immunotherapies

Abstract: Hemophilia A is an X-linked recessive bleeding disorder due to either a lack of or greatly reduced activity in the blood coagulation protein factor VIII (FVIII), due to mutations in the F8 gene. This poses significant challenges for FVIII replacement therapy since hemophilic patients are not immunologically tolerant to the protein. Thus, a proportion of patients who receive plasma-derived or recombinant FVIII replacement therapy develop anti FVIII neutralizing antibodies, known as "inhibitors." These patients require long-term regimens of high dose FVIII administration, which has varying success rates and prohibitive costs. Therefore, therapeutics for tolerance induction in such patients with inhibitors are desired. In this review, we address the current progress of immunotherapies for inducing FVIII specific tolerance in animal models of hemophilia A. Specifically we discuss the beneficial effects of B-cell depletion on immune tolerance induction (ITI), B-cell mediated gene therapy, antigen-coupled lymphocyte therapy, and regulatory T-cell epitopes (Tregitopes). ... Read more

Advances in Immune Regulation in Transplantation

Abstract: In the last three decades, we have observed a substantial progress in the organ and cell transplantation. New immune suppressive agents including calcineurin blockers and mTOR inhibitors improved transplantation outcome, but two key problems -- rejection of transplanted organs and graft versus host disease (GVHD) -- continue to be main obstacles after transplantation. Immune response is regulated with coordination of a varying number of cells. T regulatory cells orchestrate other cell responses and eventually limit immune activation and induce immune tolerance. Stimulation of negative costimulatory molecules and adoptive transfer of immunosuppressive cells including regulatory cells are promising therapies that would improve outcome of patients with organ or cell transplantation. ... Read more

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