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Medical Specialties / Transplantation / Allogeneic Stem Cell Transplantation


Immunotherapy with Chimeric Antigen Receptors for Multiple Myeloma

Abstract: Chimeric antigen receptors (CARs) are synthetic transmembrane proteins that are used to redirect autologous T cells with a new specificity for antigens on the surface of cancer cells. Impressive results from early phase clinical trials of anti-CD19 CARs for B cell malignancies have generated great enthusiasm for developing this approach for other diseases, particularly hematologic malignancies. Here we review efforts to develop CARs for the treatment of multiple myeloma. Clinical trials are underway investigating CARs against Kappa light chain, CD138, and Lewis Y antigen. CARs against BCMA, CS1, and CD38 are in pre-clinical testing. While initial clinical trials of novel CARs will focus on relapsed/refractory disease, CARs will also likely be studied as a consolidation strategy after response to first-line therapy or in conjunction with autologous hematopoietic stem cell transplantation. ... Read more

Advances in Cellular Therapy for the Treatment of Leukemia

Abstract: Adoptive immunotherapy in the form of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a treatment modality for acute and chronic leukemias that has been in practice for several decades. Drawbacks to transplantation include toxicity from chemotherapy/radiation conditioning regimens, additional toxicity from graft versus host disease, and reliance on appropriate human leukocyte antigen matched donors. Newer modalities with increased specificity of donor cells to tumor cells in addition to therapies that do not require engraftment for anti-tumor effect reduce the risk of graft versus host disease and may create a more robust graft versus leukemia response. Without the need for engraftment, or at the very least in the absence of a 100% engraftment requirement, conditioning regimens may be minimized. Three methods of adoptive immunotherapy that may offer some of these advantages over traditional transplantation are donor lymphocyte infusions (DLI), chimeric antigen receptor modified T cells (CAR T cells), and cellular immunotherapy. DLIs and cellular therapy consist of transfusing T lymphocytes from the donor to recipient in an unmanipulated form. Alternatively, donor T lymphocytes can be modified with addition of chimeric antigen receptors for specific antigen directed killing of tumor cells. Significant responses and survival benefit have been reported with these modalities. Herein, we review the mechanisms for these newer adoptive immune therapies, clinical indications for their use, and potential future directions. ... Read more

Advances in Chimeric Antigen Receptor Immunotherapy for Neuroblastoma

Abstract: Neuroblastoma (NBL) is the most common extracranial pediatric solid tumor and has heterogeneous biology and behavior. Patients with high-risk disease have poor prognosis despite complex multimodal therapy; therefore, novel curative approaches are needed. Immunotherapy is a novel therapeutic approach that harnesses the inherent activity of the immune system to control and eliminate malignant cells. One form of immunotherapy uses chimeric antigen receptors (CAR) to target tumor-associated antigens. CARs are derived from the antigen-binding domain of a monoclonal antibody (MAb) coupled with the intracellular signaling portion of the T cell receptor. CARs can combine the specificity and effectiveness of MAbs with the active bio-distribution, direct cytotoxicity, and long-term persistence of T cells. NBL provides an attractive target for CAR immunotherapy as many of its tumor-associated antigens are not expressed at significant levels on normal tissues, thus decreasing potential treatment related toxicity. Two previous clinical trials utilizing L1-cell adhesion molecule (L1-CAM) and disialoganglioside (GD2) specific CARs (GD2-CAR) have demonstrated safety and anti-tumor efficacy in heavily pretreated relapsed/refractory neuroblastoma patients. Based on these promising results and on improved techniques that can further potentiate CAR therapies, two clinical trials are currently investigating the use of GD2-CARs in children with NBL. Several approaches may further enhance anti-tumor activity and persistence of CAR modified cells, and if these can be safely translated into the clinic, CAR-based immunotherapy could become a viable adjunct or potential alternative to conventional treatment options for patients with NBL. ... Read more

Advances in Hematopoietic Stem Cell Transplantation in Chronic Myeloid Leukemia

Abstract: Treatment of chronic myeloid leukemia (CML) has evolved dramatically with the development of tyrosine kinase inhibitors (TKIs). This past decade also witnessed major advances in the field of allogeneic hematopoietic stem cell transplantation (alloHSCT) that led to better patients' outcomes. Progress in the exploitation of alternative sources of stem cells, development of novel conditioning regimens, discovery of innovative graft-versus-host prophylactic strategies, and advances in supportive care as well as positioning of alloHSCT in the overall management of CML are discussed in this article. ... Read more

Recent Advances in Haploidentical Stem Cell Transplantation

Abstract: In the last two decades, new developments in haploidentical hematopoietic stem cell transplantation have made it a viable alternative donor option. Initially, allogeneic HSCT was limited to patients who had HLA-identical related donors. To provide options for patients lacking a matched related donor, registries of unrelated volunteer donors or cord blood units have been established with the hopes of providing a phenotypically well-matched stem cell product. The use of haploidentical donors broadens the application of HSCT more than these other approaches. In addition, the greater HLA mismatching associated with haploidentical HSCT may potentiate graft versus tumor (GVT) effects. ... Read more

Marching Towards Regenerative Cardiac Therapy with Human Pluripotent Stem Cells

Abstract: Damage in cardiac tissues from ischemia or other pathological conditions leads to heart failure; and cell loss or dysfunction in pacemaker tissues due to congenital heart defects, aging, and acquired diseases can cause severe arrhythmias. The promise of successful therapies with stem cells to treat these conditions has remained elusive to the scientific community. However, recent advances in this field have opened new opportunities for regenerative cardiac therapy. Transplantation of cardiomyocytes derived from human pluripotent stem cells has the potential to alleviate heart disease. Since the initial derivation of human embryonic stem cells, significant progress has been made in the generation and characterization of enriched cardiomyocytes and the demonstration of the ability of these cardiomyocytes to survive, integrate, and function in animal models. The scope of therapeutic potential from pluripotent stem cell-derived cardiomyocytes has been further expanded with the invention of induced pluripotent stem cells, which can be induced to generate functional cardiomyocytes for regenerative cardiac therapy in a patient specific manner. The reprogramming technology has also inspired the recent discovery of direct conversion of fibroblasts into cardiomyocyte-like cells, which may allow endogenous cardiac repair. Regenerative cardiac therapy with human pluripotent stem cells is now moving closer to clinic testing. ... Read more

Advanced Therapies Using Autologous Bone Marrow Cells for Chronic Liver Disease

Abstract: The radical treatment currently for decompensated liver cirrhosis is still liver transplantation. However, liver transplants are not widely performed worldwide and development of genuine regeneration therapy for liver cirrhosis is an urgent task. We have developed a novel murine model [the green fluorescent protein (GFP)/carbon tetrachloride (CCl4) model], and reported that infused GFP-positive bone marrow cells repopulated cirrhotic liver. Moreover, repopulated bone marrow cells ameliorated liver fibrosis through higher expression of matrix metalloproteinase-9, consistent with improved liver functions and better survival rate. Based on these findings, we started a clinical trial of autologous bone marrow cell infusion (ABMi) therapy for decompensated liver cirrhotic patients, and reported the efficacy and the safety of this approach. On the other hand, various other clinical studies for liver disease have been also reported, including hepatic administration of autologous CD34-positive cells induced by granulocyte colony-stimulating factor (G-CSF), portal vein administration of CD133-positive mononuclear cells, and administration of autologous bone marrow derived mesenchymal stem cells (MSCs). Effectiveness of these approaches has been shown in some patients. We provided here an overview of the current status of liver regeneration therapies including our results of the murine GFP/CCl4 model and ABMi therapy for liver cirrhosis and future prospects. ... Read more

Emerging Techniques to Treat Limbal Epithelial Stem Cell Deficiency

Abstract: Visual performance, to a large extent, depends on the optical and refractive properties of the eye. The cornea is of great importance to this system. However, it requires a healthy epithelium for protection and optimal functioning. A sophisticated apparatus which relies on unipotent stem cells ensures the homeostasis of the corneal epithelium. A number of pathologic conditions can damage this mechanism, thereby compromising the ocular surface. This article will examine the concepts underlying a healthy or diseased corneal surface. Subsequently, current therapeutic approaches to regenerate a healthy epithelium and potential future developments will be discussed. ... Read more

Epigenetics and Transplantation: Clinical Applications of Chromatin Regulation

Abstract: Epigenetics is a field that has swiftly gained momentum over the past few years. It has been associated with applications in development, evolution and pathogenesis. In recent studies, however, a link has surfaced that connects epigenetic changes and transplantation. From its very beginning, transplantation medicine has been confronted with the looming specter of transplant rejection. It has been shown that epigenetic changes are at least partly involved in transplant outcomes; it is therefore of great importance to further investigate the exact mechanisms affecting transplantation outcome. The use of epigenetic markers for the determination of graft prognosis and the diagnosis of transplant rejection status promises to be an efficient and accurate means in clinical applications. As will be discussed in this review, enlisting the help of epigenetic mechanisms might not only facilitate the diagnosis of graft rejection, but also contribute to attenuation of transplant rejection. This would be a very desirable aid to the field of transplant medicine. ... Read more

New Classification of Acute Myeloid Leukemia and Precursor-related Neoplasms: Changes and Unsolved Issues

Abstract: The World Health Organization (WHO) classification of lympho-hematopoietic neoplasms is increasingly based on genetic criteria. Here, we focus on changes that, as compared to the 2001 edition, were introduced into the 2008 WHO classification of acute myeloid leukemia (AML) and related precursor neoplasms. The category of AML with recurrent genetic abnormalities was expanded to account for 60% of AML by adding three distinct entities, i.e., AML with t(6,9), inv(3), or t(1;22), and two provisional entities, i.e., AML with mutated NPM1 or CEBPA. These changes have greatly modified the approaches to diagnosis and prognostic stratification of AML patients. To emphasize the need of various parameters for diagnosis, including myelodysplasia (MD)-related cytogenetic abnormalities, history of myelodysplasia or myelodysplasia/myeloproliferative neoplasm, and multilineage dysplasia, the category of "AML with multilineage dysplasia" was re-named AML with MD-related changes. Finally, we describe the unique characteristics of myeloid proliferations associated with Down syndrome and blastic plasmacytoid dendritic cell neoplasm. ... Read more

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