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Medical Specialties / Oncology / Leukemia

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

Hematopoietic Cell Transplantation in Chronic Myeloid Leukemia in the Age of Tyrosine Kinase Inhibitors

Abstract: The development and widespread use of tyrosine kinase inhibitors (TKIs) has relegated the use of hematopoietic cell transplant (HCT), in most countries, to chronic myeloid leukemia (CML) patients who fail or are intolerant to TKIs. Its long-term cost effectiveness compared to TKIs, however, has maintained its use as front-line treatment in some areas. Advances in HCT, including the development of intravenous busulfan and plasma assays permitting dose adjustment, have improved results of HCT in CML. Improved supportive care has lowered the incidence of non-relapse mortality and improved survival. The availability of reduced-intensity preparative regimens, molecular typing of unrelated donors, and the use of cord blood and haploidentical donors has expanded the application of HCT to nearly any patient with an appropriate indication. From 2006 to 2010, approximately one thousand HCTs were performed annually in patients with CML. Better understanding of recent advances will improve the appropriate use and results of HCT in patients with CML. ... Read more

Targeted Therapy for Hereditary Cancer Syndromes: Neurofibromatosis Type 1, Neurofibromatosis Type 2, and Gorlin Syndrome

Abstract: Hereditary cancer syndromes are well known in the oncology community, typically affecting children, adolescents, and young adults and thereby resulting in great cumulative morbidity and mortality. These syndromes often lag behind their de novo counterparts in the development of approved novel treatment options due to their rarity in the general population. Recent work has allowed the identification of molecular aberrations and associated targeted therapies that may effectively treat these conditions. In this review, we seek to characterize some of the involved aberrations and associated targeted therapies for several germline malignancies, including Neurofibromatosis types 1 and 2, and Gorlin syndrome. Though patients with hereditary cancer syndromes may be too rare to effectively include in large clinical trials, by understanding the pathophysiology of these diseases, clinicians can attain insights into the use of targeted therapies in their own practice when treating affected individuals. ... Read more

Challenges to Chimeric Antigen Receptor (CAR)-T Cell Therapy for Cancer

Abstract: Chimeric antigen receptor (CAR)-expressing T cells have demonstrated potent clinical efficacy in patients with B cell malignancies. However, the use of CAR-T cell therapy targeting other cancers has, in part, been limited by both the induction of antigen-specific toxicities targeting normal tissues expressing the target-antigen, and the extreme potency of CAR-T cell treatments resulting in life-threatening cytokine-release syndromes. Herein, we discuss toxicities associated with CAR-T cell therapy in the clinic. Further, we discuss potential clinical interventions to ameliorate these toxicities and the application of preclinical animal models to predict the clinical utility of CAR-T cell therapy. ... 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 Chronic Lymphocytic Leukemia

Abstract: Despite the recent advances with targeted therapies in chronic lymphocytic leukemia (CLL), allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option. However, this procedure is associated with significant morbidity and mortality due to high rates of infection and the toxicity of graft versus host disease (GVHD). One of the principle aims of cellular immunotherapy is to target the malignant cells without damaging the other tissues of the body. T lymphocytes offer the opportunity to do this, due to the exquisite specificity that they exhibit as part of the adaptive immune response. Chimeric antigen receptor (CAR) T cells are lymphocytes that have been genetically modified to express the antigen binding component of an immunoglobulin molecule coupled to T-cell signaling domains. The use of an immunoglobulin molecule eliminates MHC restriction, enabling the same CAR to be used for several different patients and increasing the feasibility of widespread clinical use. They can be constructed to target a huge range of antigens, allowing the targeting of cancer cells with unprecedented levels of specificity. The addition of co-stimulatory domains to the CAR construct has enhanced the efficacy and durability of these T cells, which are under investigation in several clinical trials. The early results from these trials have been very encouraging with dramatic responses being observed in heavily pre-treated patients with otherwise poor risk disease. ... Read more

Integration of Genomics into Medical Practice

Abstract: Although some have wondered whether the sequencing of the human genome has led to major advances in medicine, in fact there are multiple examples where genomics has been integrated into medical practice. In the area of prevention, genomic approaches are now used for non-invasive prenatal testing of fetal DNA in the maternal circulation, for expanded preconceptional screening for carrier status, for autosomal recessive disorders, and for assessment of risk of common disease. In the area of diagnosis, major advances have been made in cytogenomics and in use of whole exome or whole genome sequencing. In therapeutics, pharmacogenetic testing is now feasible, tumor genome sequencing is being used to guide cancer therapy, and genomic discoveries are enabling development of new targeted therapies. Ultimately it is possible that genome sequencing may be done for all individuals on a routine basis, though there remain significant technical, ethical, and medical systems challenges to be overcome. It is likely that integration of genomics into medical practice will occur gradually over a long period of time, but the process is now well underway. ... 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

Tumor and T Cell Engagement by BiTE

Abstract: Cancer immunotherapy attempts to exploit the capability of the immune system to attack malignant cells. Recent results suggest that clinical responses in patients point to this new mechanism as potentially beneficial in harnessing the immune system for combating established malignancies. These checkpoint-related immunotherapies rely on engaging a subset of T cells in anti-tumor immune responses. BiTE® (Bi-specific T cell engager) represents a distinct modality that directly engages any T cell and a specific antigen expressing tumor cell. The approach offers the advantage of engaging T cells and patient tumor cells that differentially express a specific cell surface antigen. The specificity confers redirected tumor cell killing and recent clinical data with the BiTE blinatumomab show evidence of clinical remissions. The characteristics of a suitable BiTE with the benefit of CD3 mediated T cell recognition and articulation of tumor specific antigens combined in this therapeutic modality is described here. ... Read more

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