ige-antibody-dependent immunotherapy of solid tumors: cytotoxic

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    Cancer CellsMechanisms of Eradication of OvarianSolid Tumors: Cytotoxic and Phagocytic IgE-Antibody-Dependent Immunotherapy of

    Balkwill and Hannah J. GouldBurke, Robert J. Moore, David D. Dombrowicz, Frances R. David J. Fear, Richard G. Thompson, Nicholas East, FrancesNatalie McCloskey, Rebecca L. Beavil, Andrew J. Beavil, Sophia N. Karagiannis, Marguerite G. Bracher, James Hunt,

    http://www.jimmunol.org/content/179/5/2832doi: 10.4049/jimmunol.179.5.2832

    2007; 179:2832-2843; ;J Immunol


    , 27 of which you can access for free at: cites 68 articlesThis article


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    Print ISSN: 0022-1767 Online ISSN: 1550-6606. Immunologists All rights reserved.Copyright 2007 by The American Association of1451 Rockville Pike, Suite 650, Rockville, MD 20852The American Association of Immunologists, Inc.,

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  • IgE-Antibody-Dependent Immunotherapy of Solid Tumors:Cytotoxic and Phagocytic Mechanisms of Eradication ofOvarian Cancer Cells1,2

    Sophia N. Karagiannis,3* Marguerite G. Bracher,* James Hunt,* Natalie McCloskey,*Rebecca L. Beavil,* Andrew J. Beavil,* David J. Fear,* Richard G. Thompson, Nicholas East,

    Frances Burke, Robert J. Moore, David D. Dombrowicz, Frances R. Balkwill,

    and Hannah J. Gould*

    Abs have a paramount place in the treatment of certain, mainly lymphoid, malignancies, although tumors of nonhemopoieticorigin have proved more refractory ones. We have previously shown that the efficacy of immunotherapy of solid tumors, inparticular ovarian carcinoma, may be improved by the use of IgE Abs in place of the conventional IgG. An IgE Ab (MOv18 IgE)against an ovarian-tumor-specific Ag (folate binding protein), in combination with human PBMC, introduced into ovarian cancerxenograft-bearing mice, greatly exceeded the analogous IgG1 in promoting survival. In this study, we analyzed the mechanismsby which MOv18 IgE may exert its antitumor activities. Monocytes were essential IgE receptor-expressing effector cells thatmediated the enhanced survival of tumor-bearing mice by MOv18 IgE and human PBMC. Monocytes mediated MOv18 IgE-dependent ovarian tumor cell killing in vitro by two distinct pathways, cytotoxicity and phagocytosis, acting respectively throughthe IgE receptors FcRI and CD23. We also show that human eosinophils were potent effector cells in MOv18 IgE Ab-dependentovarian tumor cell cytotoxicity in vitro. These results demonstrate that IgE Abs can engage cell surface IgE receptors and activateeffector cells against ovarian tumor cells. Our findings offer a framework for an improved immunotherapeutic strategy forcombating solid tumors. The Journal of Immunology, 2007, 179: 28322843.

    O varian cancer ranks second among gynecological can-cers in the number of new cases and first in the numberof deaths each year (1, 2). In the early stages, it grows inand around the ovaries and it metastasizes in the peritoneal cavityand later to the internal organs. It causes no symptoms in the earlystages, and is essentially incurable in the late stages of the disease;around 5060% of patients die within 5 years (1, 2). Ovariancancer is intractable to current chemotherapies, but immunother-apies using IgG Abs currently in clinical trials are showing somepromising results (36).

    The current use of the IgG1 Ab isotype in Ab immunotherapystems from Waldmanns classic work (7, 8) on the efficacy of

    Campath-1H (alemtuzumab) IgG Ab subclasses in complement-dependent immunotherapy of non-Hodgkins lymphoma. Severalother mechanisms are now known to operate in Ab immunother-apies (3, 9). However, non-IgG isotypes have never been tried incancer patients. IgG Abs are now increasingly being used for thetreatment of blood malignancies, but solid tumors are often re-fractory (35). Probable reasons are diffusional barrier of tissues,slow recruitment of effector cells, and low affinity of IgG for itsreceptors (810).

    Abs of the IgE class may offer an alternative to the conventionaltreatments with IgG Abs, particularly for solid tumors such asthose of the ovary. Unlike Abs of the IgG class, IgE binds to itsreceptors with very high affinity. The affinity of IgE for its highaffinity receptor, FcRI (Ka 10

    11 M1), is two to five orders ofmagnitude higher than that of IgG for the FcRs (FcRI-III) (911). Its affinity for the low affinity receptor, CD23 (Ka 10


    M1), is as high as that of IgG for FcRI (11). Furthermore, theperitoneal cavity, where ovarian cancer spreads, is home to IgEreceptor-expressing cells, such as macrophages (12, 13), mast cells(14), and dendritic cells (15). These properties may translate tostrong retention of Abs in tissues and longer antitumor immunesurveillance. IgE may therefore have greater efficacy than IgG intargeting tumors in nonhemopoietic tissues.

    A number of epidemiological studies on the relation betweenallergies and the risk of cancer support the idea that IgE mighthave advantages over IgG for the treatment of certain types ofcancer. Mills et al. (16) conducted a prospective study in 34,198Seventh-Day Adventists. They found that the risk of prostate,breast cancer, and lymphatic or hematopoetic cancers actually in-creased with allergy, and further increased with an increasing num-ber of allergies. However, the risk of ovarian cancer was de-creased with allergy and decreased with an increasing number of

    *Randall Division of Cell and Molecular Biophysics, New Hunts House, KingsCollege London, Guys Campus, London, United Kingdom; Centre for TranslationalOncology, Institute of Cancer and the CR-UK Clinical Centre, Barts and The London,Queen Marys School of Medicine and Dentistry, John Vane Science Centre, Char-terhouse Square, London, United Kingdom; and Institut National de la Sante et de laRecherche Medicale, Institut Federatif de Recherche 17, Institut Pasteur de Lille,Unite 547, Lille, France

    Received for publication February 15, 2007. Accepted for publication June 28, 2007.

    The costs of publication of this article were defrayed in part by the payment of pagecharges. This article must therefore be hereby marked advertisement in accordancewith 18 U.S.C. Section 1734 solely to indicate this fact.1 This study was supported by the Association for International Cancer Re-search, U.K.2 The costs of publication of this article were defrayed in part by the payment of pagecharges. This article must therefore be hereby marked advertisement in accordancewith 18 U.S.C. section 1734 solely to indicate this fact.3 Address correspondence and reprint requests to Dr. Sophia N. Karagiannis, RandallDivision of Cell and Molecular Biophysics, Kings College London, Room 3.8, NewHunts House, Guys Campus, St Thomass Street, London, U.K. E-mail address:sophia.karagiannis@kcl.ac.uk

    Copyright 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00

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  • allergies. A recent meta-analysis has demonstrated a significantinverse association between a history of both asthma and hay feverand overall cancer mortality and colorectal cancer (17). Recentstudies have also confirmed the increased risk of prostate andbreast cancer (18), and shown an increased risk for lung cancerwith asthma and a decreased risk of pancreatic cancer and glioma(1924).

    Experimental studies have also supported the concept of har-nessing IgE for cancer therapy. Nagy et al. (25) demonstrated thata mouse monoclonal IgE, directed against the murine mammarytumor virus, prevented the growth of the tumor in mice. Kershawet al. (26) showed that a mouse monoclonal IgE, directed againsta human colon carcinoma Ag, conferred a brief survival advantageto mice implanted with colon tumor cells. We have shown that achimeric Ab, MOv18 IgE, directed against an ovarian tumor Ag,folate binding protein, in combination with human PBMC, wasmore active than MOv18 IgG1 in protection of mice from ovariantumor growth in two xenograft models of ovarian carcinoma inscid and nude mice (27, 28).

    T cells do not express FcRI, and hence treatment with IgE Abswould not exploit their known cytotoxic functions. Kershaw et al.(29) expressed the extracellular portion of the high-affinity IgEreceptor, FcRI -chain, joined to the membrane sequence ofmouse FcRII and cytoplasmic sequences of CD28


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