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

Details

Serval ID
serval:BIB_34C385A84969
Type
Article: article from journal or magazin.
Collection
Publications
Title
Identifying alemtuzumab as an anti-myeloid cell antiangiogenic therapy for the treatment of ovarian cancer.
Journal
Journal of Translational Medicine
Author(s)
Pulaski H.L., Spahlinger G., Silva I.A., McLean K., Kueck A.S., Reynolds R.K., Coukos G., Conejo-Garcia J.R., Buckanovich R.J.
ISSN
1479-5876 (Electronic)
ISSN-L
1479-5876
Publication state
Published
Issued date
2009
Volume
7
Pages
49
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: epublish
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 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.
Keywords
Angiogenesis Inhibitors/immunology, Angiogenesis Inhibitors/pharmacology, Animals, Antibodies, Monoclonal/therapeutic use, Antibodies, Monoclonal, Humanized, Antibodies, Neoplasm/therapeutic use, Antigens, CD/metabolism, Antigens, Neoplasm/metabolism, Antineoplastic Agents/therapeutic use, Complement System Proteins/metabolism, Female, Glycoproteins/metabolism, Humans, Immunotherapy/methods, Mice, Mice, Inbred C57BL, Myeloid Cells/drug effects, Myeloid Cells/pathology, Neoplasm Transplantation/immunology, Ovarian Neoplasms/immunology, Ovarian Neoplasms/pathology, Random Allocation, Receptor Protein-Tyrosine Kinases/metabolism, Receptor, TIE-2/metabolism, Xenograft Model Antitumor Assays
Pubmed
Web of science
Open Access
Yes
Create date
14/10/2014 12:43
Last modification date
20/08/2019 14:21
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