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Combining Antiangiogenic Therapy with Adoptive Cell Immunotherapy Exerts Better Antitumor Effects in Non-Small Cell Lung Cancer Models

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      Abstract

      IntroductionCytokine-induced killer cells (CIK cells) are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment.MethodsWe combined recombinant human endostatin (rh-endostatin) and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells.ResultsOur results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments.ConclusionsOur results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells therapy against lung carcinomas and unmask the mechanisms of the synergistic antitumor efficacy, providing a new rationale for combining antiangiogenesis therapy with immunotherapy in the treatment of lung cancer.

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      Most cited references 41

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      Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. A total of 1,638,910 new cancer cases and 577,190 deaths from cancer are projected to occur in the United States in 2012. During the most recent 5 years for which there are data (2004-2008), overall cancer incidence rates declined slightly in men (by 0.6% per year) and were stable in women, while cancer death rates decreased by 1.8% per year in men and by 1.6% per year in women. Over the past 10 years of available data (1999-2008), cancer death rates have declined by more than 1% per year in men and women of every racial/ethnic group with the exception of American Indians/Alaska Natives, among whom rates have remained stable. The most rapid declines in death rates occurred among African American and Hispanic men (2.4% and 2.3% per year, respectively). Death rates continue to decline for all 4 major cancer sites (lung, colorectum, breast, and prostate), with lung cancer accounting for almost 40% of the total decline in men and breast cancer accounting for 34% of the total decline in women. The reduction in overall cancer death rates since 1990 in men and 1991 in women translates to the avoidance of about 1,024,400 deaths from cancer. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population, with an emphasis on those groups in the lowest socioeconomic bracket. Copyright © 2012 American Cancer Society, Inc.
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        Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.

         R Jain (2005)
        Solid tumors require blood vessels for growth, and many new cancer therapies are directed against the tumor vasculature. The widely held view is that these antiangiogenic therapies should destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. Here, I review emerging evidence supporting an alternative hypothesis-that certain antiangiogenic agents can also transiently "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery. Drugs that induce vascular normalization can alleviate hypoxia and increase the efficacy of conventional therapies if both are carefully scheduled. A better understanding of the molecular and cellular underpinnings of vascular normalization may ultimately lead to more effective therapies not only for cancer but also for diseases with abnormal vasculature, as well as regenerative medicine, in which the goal is to create and maintain a functionally normal vasculature.
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          Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols.

          We describe a standard set of quantity names and symbols related to the estimation of kinetic parameters from dynamic contrast-enhanced T(1)-weighted magnetic resonance imaging data, using diffusable agents such as gadopentetate dimeglumine (Gd-DTPA). These include a) the volume transfer constant K(trans) (min(-1)); b) the volume of extravascular extracellular space (EES) per unit volume of tissue v(e) (0 < v(e) < 1); and c) the flux rate constant between EES and plasma k(ep) (min(-1)). The rate constant is the ratio of the transfer constant to the EES (k(ep) = K(trans)/v(e)). Under flow-limited conditions K(trans) equals the blood plasma flow per unit volume of tissue; under permeability-limited conditions K(trans) equals the permeability surface area product per unit volume of tissue. We relate these quantities to previously published work from our groups; our future publications will refer to these standardized terms, and we propose that these be adopted as international standards.
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            Author and article information

            Affiliations
            Medical Oncology Department of Jinling Hospital, Medical school of Nanjing University, Nanjing, People’s Republic of China
            Wayne State University, United States of America
            Author notes

            Competing Interests: The authors have declared that no competing interests exist.

            Conceived and designed the experiments: SJS RW LBC GCH. Performed the experiments: SJS GCH RW YTC HZS. Analyzed the data: SJS HZS GCH YTC. Contributed reagents/materials/analysis tools: SJS YTC HZS. Wrote the paper: SJS LBC GCH RW.

            Contributors
            Role: Editor
            Journal
            PLoS One
            PLoS ONE
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, USA )
            1932-6203
            2013
            14 June 2013
            : 8
            : 6
            23799045
            3683034
            PONE-D-12-37570
            10.1371/journal.pone.0065757
            (Editor)

            This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

            Counts
            Pages: 15
            Funding
            The work was supported by National Natural Science Foundation of China (Grant number: 81101739) and China International Medical Foundation (Grant number: CIMF-F-H001-023). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Biology
            Model Organisms
            Animal Models
            Mouse
            Medicine
            Oncology
            Basic Cancer Research
            Immune Evasion
            Tumor Physiology
            Cancer Treatment
            Antiangiogenesis Therapy
            Immunotherapy
            Cancers and Neoplasms
            Lung and Intrathoracic Tumors
            Small Cell Lung Cancer

            Uncategorized

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