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


CONCLUSIONS
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.
Pulaski
Heather L
HL
Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, USA. heascott@umich.edu
Spahlinger
Gregory
G
Silva
Ines A
IA
McLean
Karen
K
Kueck
Angela S
AS
Reynolds
R Kevin
RK
Coukos
George
G
Conejo-Garcia
Jose R
JR
Buckanovich
Ronald J
RJ
D000074323:Alemtuzumab; D020533:Angiogenesis Inhibitors / Q000276:immunology / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000074301:CD52 Antigen; D003165:Complement System Proteins / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects* / Q000473:pathology; D009368:Neoplasm Transplantation / Q000276:immunology; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011897:Random Allocation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D006023:Glycoproteins; D000074323:Alemtuzumab; D003165:Complement System Proteins; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2