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Medical Specialties / Oncology / Leukemia


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

Novel Therapeutic Agents for T-cell Lymphomas

Abstract: T-cell lymphomas are a heterogeneous group of T-cell malignancies arising from post-thymic mature T-cells. Together they account for 10-15% of all non-Hodgkin's lymphoma. Because of the different underlying pathology, different T-cell lymphoma subtypes may require different treatment approaches. In general, the treatment results of T-cell lymphomas, using conventional anthracycline-based combination chemotherapy, are disappointing. Though autologous or allogeneic stem cell transplantation may offer a cure to some of the patients, a substantial proportion of patients are not eligible for transplantation because of the chemo-refractoriness or short remission duration of the lymphomas. Novel therapies may open up the potential path for better disease control. We review several classes of novel treatment for T-cell lymphomas including monoclonal antibodies, epigenetic modifiers, newer generation of cytotoxics, and specific targeting agents that may improve treatment outcome. ... Read more

Novel Targeted Therapies in Peripheral T Cell Lymphoma

Abstract: Peripheral T cell lymphomas (PTCL), non-Hodgkin lymphomas characterized by having features of T cells that have matured in the thymus, are a heterogeneous group of clinical entities. Compared with B cell lymphomas, they are less common, more difficult to diagnose and classify, more aggressive, and have inferior outcomes with current treatment paradigms. They are also less completely understood in terms of how different PTCL types correspond to normal T cell development, and in identifying cell signaling pathways as targets for new therapies. Recent studies with novel targeted therapies as single agents or in combination with other drugs have illustrated promising outcomes both for relapsed and frontline PTCL. We first briefly review classification, prognostic indices, and results of initial therapy of various T cell lymphomas. We then review recent studies of chemotherapy, monoclonal antibody-based therapy directed at cell surface targets, small molecule inhibitors of intracellular targets such as histone deacetylases and the proteasome, and agents that disrupt stromal interactions. Investigations that enhance our knowledge of T cell molecular biology and integrate novel targeted agents into the treatment algorithm for PTCL will be keys to improved outcomes for patients with PTCL. ... Read more

Personalized Cancer Treatment and the Myth of KRAS Wild-type Colon Tumors

Abstract: The impact of KRAS mutations on the efficacy of therapies that target the epidermal growth factor receptor (EGFR) is a major, ongoing area of oncology research, aimed at identifying the best possible treatments for individual colon cancer patients. Because patients with KRAS mutant colorectal tumors rarely respond to anti-EGFR monoclonal antibodies, testing is required to confirm the patient's tumor is KRAS wild-type before utilizing these therapies. Despite being studied for more than 30 years, new information continues to develop regarding KRAS and its role in colon carcinogenesis. This information must be integrated into the development of effective colon cancer treatment strategies. This review will summarize recent evidence that most, if not all, colon tumors encompass at least a subpopulation of KRAS mutant cells, meaning tumors characterized as KRAS wild-type are in most cases tumors with relatively low KRAS mutant tumor cell content. Recent studies support the hypothesis that relapse in advanced colorectal patients treated with EGFR-targeted monoclonal antibody therapy involves the outgrowth of previously undetected KRAS mutant tumor cell populations. Studies investigating the effects of oxidative stress on Ras signaling suggest that the frequent presence of minor KRAS mutant tumor cell populations may be a consequence of hypoxic conditions within tumors, which produce a negative selection against KRAS mutant cells in polyclonal tumors. Thus, the literature and current practices for characterizing tumor KRAS mutation don't accurately reflect the nature of colon tumor KRAS mutation, even though an accurate understanding is critical for identifying the best strategies for intervention. ... Read more

Adherence to Targeted Oral Anticancer Medications

Abstract: The use of targeted oral anticancer medications (OAMs) is becoming increasingly prevalent in cancer care. Approximately 25-30% of the oncology drug pipeline involves oral agents and there are now over 50 OAMs approved by the Food and Drug Administration. This change represents a major shift in management of patients with cancer from directly observed, intermittent intravenous therapy to self-administered, oral chronic therapy. The increased prevalence of OAMs raises the issue of adherence in oncology, including understanding the challenges of adherence to OAMs. This review focuses on studies of adherence for patients taking molecularly targeted OAMs for breast cancer, chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GIST), non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). We then discuss barriers to adherence and studies performed to date testing interventions for improving adherence. Finally, we discuss future areas of investigation needed to define and improve adherence to OAMs in targeted therapy for cancer. ... Read more

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