Identifying alemtuzumab as an anti-myeloid cell antiangiogenic therapy for the treatment of ovarian cancer

Pulaski, Spahlinger Gregory, Silva, Mclean Karen, Kueck, Reynolds, Coukos George, Conejo-Garcia, Buckanovich

Description

Murine studies suggest that myeloid cells such as vascular leukocytes (VLC) and Tie2 + monocytes play a critical role in tumor angiogenesis and vasculogenesis. Myeloid cells are a primary cause of resistance to anti-VEGF therapy. The elimination of these cells from the tumor microenvironment significantly restricts tumor growth in both spontaneous and xenograft murine tumor models. Thus animal studies indicate that myeloid cells are potential therapeutic targets for solid tumor therapy. Abundant VLC and Tie2 + monocytes have been reported in human cancer. Unfortunately, the importance of VLC in human cancer growth remains untested as there are no confirmed therapeutics to target human VLC. Methods We used FACS to analyze VLC in ovarian and non-ovarian tumors, and characterize the relationship of VLC and Tie2-monocytes. We performed qRT-PCR and FACS on human VLC to assess the expression of the CD52 antigen, the target of the immunotherapeutic Alemtuzumab. We assessed Alemtuzumab's ability to induce complement-mediated VLC killing in vitro and in human tumor ascites. Finally we assessed the impact of anti-CD52 immuno-toxin therapy on murine ovarian tumor growth. Results Human VLC are present in ovarian and non-ovarian tumors. The majority of VLC appear to be Tie2+ monocytes. VLC and Tie2+ monocytes express high levels of CD52, the target of the immunotherapeutic Alemtuzumab. Alemtuzumab potently induces complement-mediated lysis of VLC in vitro and ex-vivo in ovarian tumor ascites. Anti-CD52 immunotherapy targeting VLC restricts tumor angiogenesis and growth in murine ovarian cancer. Conclusion These studies confirm VLC/myeloid cells as therapeutic targets in ovarian cancer. Our data provide critical pre-clinical evidence supporting the use of Alemtuzumab in clinical trials to test its efficacy as an anti-myeloid cell antiangiogenic therapeutic in ovarian cancer. The identification of an FDA approved anti-VLC agent with a history of clinical use will allow immediate proof-of-principle clinical trials in patients with ovarian cancer.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2009
• Nombre de lectures: 15
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

Pga e 1fo1  ( 4 apegum nr bet nor foaticnoitrup esops)

Research Open Access Identifying alemtuzumab as an an ti-myeloid cell antiangiogenic therapy for the treatment of ovarian cancer Heather L Pulaski 1 , Gregory Spahlinger 2 , Ines A Silva 2 , Karen McLean 1 , Angela S Kueck 1 , R Kevin Reynolds 1 , George Coukos 3 , Jose R Conejo-Garcia 4  and Ronald J Buckanovich* 1,2

Journal of Translational Medicine Bio Med  Central

Abstract Background: Murine studies suggest that myeloid cells such as vascular leukocytes (VLC) and Tie2 + monocytes play a critical role in tumor angiogenesis and vasculogenesis . Myeloid cells are a primary cause of resistance to anti-VEGF therapy. The eliminat ion of these cells from the tumor microenvironment significantly restricts tumor growth in both sponta neous and xenograft murine tumor models. Thus animal studies indicate that myel oid cells are potential therapeutic target s for solid tumor therapy. Abundant VLC and Tie2 + monocytes have been reported in human canc er. Unfortunately, the importance of VLC in human cancer growth remains untested as there ar e no confirmed therapeutics to target human VLC. Methods: We used FACS to analyze VLC in ovarian an d non-ovarian tumors, and characterize the relationship of VLC and Tie2-mon ocytes. We performed qRT-PCR an d FACS on human VLC to assess the expression of the CD52 antigen, the target of the immunotherapeutic Al emtuzumab. We assessed Alemtuzumab's ability to induce complement-mediate d VLC killing in vitro and in human tumor ascites. Finally we assessed the impact of anti-CD52 immuno-toxin therapy on murine ovarian tumor growth. Results: Human VLC are present in ovarian and non-ovar ian tumors. The majority of VLC appear to be Tie2+ monocytes. VLC and Tie2+ monocytes express high levels of CD52, the target of the immunotherapeutic Alemtuzumab. Alemtuzumab potent ly induces complement-mediated lysis of VLC in vitro and ex-vivo in ovarian tumor ascites. Anti -CD52 immunotherapy target ing VLC restricts tumor angiogenesis and growth in murine ovarian cancer. Conclusion: These studies confirm VLC/myeloi d cells as therapeutic targets in ovarian cancer. Our data provide critical pre-clinical evidence supporting the use of Alemtuzumab in clinical trials to test its efficacy as an anti-myeloid cell antiangiogen ic therapeutic in ovarian cancer. Th e identification of an FDA approved anti-VLC agent with a histor y of clinical use will allow immediate proof-of-principle clinical trials in patients with ovarian cancer.

Published: 19 June 2009 Received: 7 January 2009 Journal of Translational Medicine 2009, 7 :49 doi:10.1186/1479-5876-7-49  Accepted: 19 June 2009 This article is available from: http://www. translational-medicine.com/content/7/1/49 © 2009 Pulaski et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the orig inal work is properly cited.

Address: 1 Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, USA, 2 Department of Internal Medicine, University of Michigan, Ann Arbor, USA, 3 Department of Obstetrics and Gynecology, Univ ersity of Pennsylvania, Philadelphia, USA and 4 Departments of Microbiology and Immunology, Dartmo uth Medical School, Hanover, USA Email: Heather L Pulaski - heas [e-mail]; Gregory Spahlinger - [e-mail]; Ines A Silva - [e-mail]; Karen McLean - [e-mail]; Angela S Kueck - [e-mail]; R Kevin Reynolds - [e-mail]; George Coukos - [e-mail]; Jose R Conejo-Garcia - [e-mail]; Ronald J Buckanovich* - [e-mail] Corresponding author *