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      The Application of Natural Killer Cell Immunotherapy for the Treatment of Cancer


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          Natural killer (NK) cells are essential components of the innate immune system and play a critical role in host immunity against cancer. Recent progress in our understanding of NK cell immunobiology has paved the way for novel NK cell-based therapeutic strategies for the treatment of cancer. In this review, we will focus on recent advances in the field of NK cell immunotherapy, including augmentation of antibody-dependent cellular cytotoxicity, manipulation of receptor-mediated activation, and adoptive immunotherapy with ex vivo-expanded, chimeric antigen receptor (CAR)-engineered, or engager-modified NK cells. In contrast to T lymphocytes, donor NK cells do not attack non-hematopoietic tissues, suggesting that an NK-mediated antitumor effect can be achieved in the absence of graft-vs.-host disease. Despite reports of clinical efficacy, a number of factors limit the application of NK cell immunotherapy for the treatment of cancer, such as the failure of infused NK cells to expand and persist in vivo. Therefore, efforts to enhance the therapeutic benefit of NK cell-based immunotherapy by developing strategies to manipulate the NK cell product, host factors, and tumor targets are the subject of intense research. In the preclinical setting, genetic engineering of NK cells to express CARs to redirect their antitumor specificity has shown significant promise. Given the short lifespan and potent cytolytic function of mature NK cells, they are attractive candidate effector cells to express CARs for adoptive immunotherapies. Another innovative approach to redirect NK cytotoxicity towards tumor cells is to create either bispecific or trispecific antibodies, thus augmenting cytotoxicity against tumor-associated antigens. These are exciting times for the study of NK cells; with recent advances in the field of NK cell biology and translational research, it is likely that NK cell immunotherapy will move to the forefront of cancer immunotherapy over the next few years.

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          Graft-versus-host disease.

          Haemopoietic-cell transplantation (HCT) is an intensive therapy used to treat high-risk haematological malignant disorders and other life-threatening haematological and genetic diseases. The main complication of HCT is graft-versus-host disease (GVHD), an immunological disorder that affects many organ systems, including the gastrointestinal tract, liver, skin, and lungs. The number of patients with this complication continues to grow, and many return home from transplant centres after HCT requiring continued treatment with immunosuppressive drugs that increases their risks for serious infections and other complications. In this Seminar, we review our understanding of the risk factors and causes of GHVD, the cellular and cytokine networks implicated in its pathophysiology, and current strategies to prevent and treat the disease. We also summarise supportive-care measures that are essential for management of this medically fragile population.
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            Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer.

            We describe here the preliminary results of the systemic administration of autologous lymphokine-activated killer (LAK) cells and the recombinant-derived lymphokine interleukin-2 to patients with advanced cancer. This regimen was based on animal models in which the systemic administration of LAK cells plus interleukin-2 mediated the regression of established pulmonary and hepatic metastases from a variety of murine tumors in several strains of mice. We treated 25 patients with metastatic cancer in whom standard therapy had failed. Patients received both 1.8 to 18.4 X 10(10) autologous LAK cells, generated from lymphocytes obtained through multiple leukaphereses, and up to 90 doses of interleukin-2. Objective regression of cancer (more than 50 per cent of volume) was observed in 11 of the 25 patients: complete tumor regression occurred in one patient with metastatic melanoma and has been sustained for up to 10 months after therapy, and partial responses occurred in nine patients with pulmonary or hepatic metastases from melanoma, colon cancer, or renal-cell cancer and in one patient with a primary unresectable lung adenocarcinoma. Severe fluid retention was the major side effect of therapy, although all side effects resolved after interleukin-2 administration was stopped. Further development of this approach and additional patient follow-up are required before conclusions about its therapeutic value can be drawn.
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              Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer.

              Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy.

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                17 November 2015
                : 6
                [1] 1Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX, USA
                [2] 2Department of Pediatrics, Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine , Houston, TX, USA
                [3] 3Center for Cell and Gene Therapy, Baylor College of Medicine Houston Methodist Hospital and Texas Children’s Hospital , Houston, TX, USA
                Author notes

                Edited by: Rafael Solana, University of Cordoba, Spain

                Reviewed by: Kamalakannan Rajasekaran, Blood Research Institute, USA; Alejandra Pera, Instituto Maimonides de Investigaciones Biomédicas de Córdoba, Spain

                *Correspondence: Katayoun Rezvani, krezvani@ 123456mdanderson.org

                Specialty section: This article was submitted to NK Cell Biology, a section of the journal Frontiers in Immunology

                Copyright © 2015 Rezvani and Rouce.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 116, Pages: 13, Words: 11271
                Funded by: Lymphoma Research Foundation 10.13039/100001219
                Award ID: 1LRF CDGA
                Funded by: Lymphoma SPORE
                Award ID: P50CA126752
                Funded by: University of Texas MD Anderson Cancer Center 10.13039/100007313
                Award ID: CA100632
                Funded by: Sister Institution Network Fund

                natural killer cells,adoptive immunotherapy,car nk cells,adcc,anti-kir antibody,nk-92,transplantation


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