Involvement of neutrophils and natural killer cells in the anti-tumor activity of alemtuzumab in xenograft tumor models.
ABSTRACT Alemtuzumab is a recombinant humanized IgG1 monoclonal antibody directed against CD52, an antigen expressed on the surface of normal and malignant B and T lymphocytes. Alemtuzumab is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), but the exact mechanism by which the antibody depletes malignant lymphocytes in vivo is not clearly defined. To address this issue, the anti-tumor activity of alemtuzumab was studied in disseminated and subcutaneous xenograft tumor models. The density of CD52 target antigen on the surface of tumor cells appeared to correlate with the anti-tumor activity of alemtuzumab. Deglycosylation of alemtuzumab resulted in a loss of cytotoxicity in vitro and was found to abolish anti-tumor activity in vivo. Individual inactivation of effector mechanisms in tumor-bearing mice indicated that the protective activity of alemtuzumab in vivo was primarily dependent on ADCC mediated by neutrophils and to a lesser extent NK cells. Increasing the number of circulating neutrophils by treatment with G-CSF enhanced the anti-tumor activity of the antibody, thus providing further evidence for the involvement of neutrophils as effector cells in the activity of alemtuzumab.
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ABSTRACT: Natural killer (NK) cells have been known to enhance the host immune responses against cancer. NK cell number and cytotoxicity in patients with cancer is often low. Therefore, we developed a large-scale ex vivo NK cell expansion method without feeder layers and introduced NK cell-based autologous immune enhancement therapy (AIET). In this paper, we discuss the epidemiological data that show the relationship between NK activity and cancer incidence, monitoring of NK cell number and activity, anti-cancer activities of NK cells in vitro and in vivo and the effects of the combination of expanded NK cells with monoclonal antibody drugs on cancers through antibody-dependent cellular cytotoxicity. Finally, we also present the clinical cases of NK cell-based AIET and the effect of AIET on advanced stage of pancreatic cancer and on various advanced cancers refractory to conventional therapies. NK cell-based AIET might be a useful strategy in the multidisciplinary approach to cancer.Journal of stem cells & regenerative medicine. 01/2013; 9(1):9-13.
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ABSTRACT: Both mycosis fungoides (MF) and Sézary syndrome (SS) have a chronic, relapsing course, with patients frequently undergoing multiple, consecutive therapies. Treatment is aimed at the clearance of skin disease, the minimization of recurrence, the prevention of disease progression, and the preservation of quality of life. Other important considerations are symptom severity, including pruritus and patient age/comorbidities. In general, for limited patch and plaque disease, patients have excellent prognosis on ≥1 topical formulations, including topical corticosteroids and nitrogen mustard, with widespread patch/plaque disease often requiring phototherapy. In refractory early stage MF, transformed MF, and folliculotropic MF, a combination of skin-directed therapy plus low-dose immunomodulators (eg, interferon or bexarotene) may be effective. Patients with advanced and erythrodermic MF/SS can have profound immunosuppression, with treatments targeting tumor cells aimed for immune reconstitution. Biologic agents or targeted therapies either alone or in combination-including immunomodulators and histone-deacetylase inhibitors-are tried first, with more immunosuppressive therapies, such as alemtuzumab or chemotherapy, being generally reserved for refractory or rapidly progressive disease or extensive lymph node and metastatic involvement. Recently, an increased understanding of the pathogenesis of MF and SS with identification of important molecular markers has led to the development of new targeted therapies that are currently being explored in clinical trials in advanced MF and SS.Journal of the American Academy of Dermatology 02/2014; 70(2):223.e1-223.e17. · 4.91 Impact Factor
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ABSTRACT: The creation of new cancer immunotherapies represents one of the most exciting advances taking place in this decade. While clinical studies continue to indicate improvement in clinical outcomes, the speed of its diffusion into actual practice is not known. It is important to understand practice variation in the utilization of recommended immunotherapies as new and more effective immunotherapies are developed. Additionally, as the field continues to grow, immunotherapy will encounter new barriers that will hinder its rapid adoption into clinical practice. This review aims to present a brief summary of the mechanisms and uses of antibody-based immunotherapies used to treat lymphoma and present available practice variation data, including factors associated with variation. Review of the available data implicated patient characteristics and healthcare system as being associated with practice variation; however, in several instances ease-of-use, cost, toxicity, and physician knowledge contributed to variation regardless of efficacy. As new immunotherapies are developed, these factors must be considered in order to increase the rapid diffusion of effective immunotherapies into wide clinical use.Clinical Lymphoma Myeloma and Leukemia. 01/2014;