Monoclonal antibody-based immunotherapy of ovarian cancer: targeting ovarian cancer cells with the B7-H3-specific mAb 376.96.
OBJECTIVE
The high rate of relapse in patients with advanced ovarian cancer likely reflects the chemoresistance of cancer initiating cells (CICs). We evaluated the anti-tumor activity of monoclonal antibody (mAb) 376.96, which recognizes a B7-H3 epitope expressed on ovarian carcinoma cells (OCCs), in combination with the tyrosine kinase inhibitor Sunitinib and chemotherapy on chemosensitive and chemoresistant cells and CICs.


METHODS
Eight ovarian cancer cell lines including platinum- and taxane-resistant cell lines were analyzed by flow cytometry to establish expression of the mAb 376.96-defined-B7-H3-epitope on differentiated ovarian cancer cells and CICs. Samples from 10 ovarian cancer patients were analyzed via immunohistochemistry for mAb 376.96-defined-B7-H3-epitope expression. In vitro studies assessed mAb 376.96 alone and in combination with Sunitinib on the growth of chemosensitive and chemoresistant cell lines and on the content of CICs.


RESULTS
The mAb-376.96-defined-B7-H3 epitope is expressed on both differentiated cells and CICs in chemosensitive and chemoresistant ovarian cancer cell lines and 10 patient derived ovarian cancer tumors. In vitro treatment of chemoresistant cell lines with mAb 376.96 resulted in decreased cell viability. mAb 376.96 enhanced the cytotoxicity of Sunitinib and reduced the content of CICs.


CONCLUSIONS
The mAb-376.96-defined-B7-H3-epitope was found to be expressed on both differentiated ovarian cancer cells and CICs in chemosensitive and chemoresistant ovarian cancer cell lines. mAb 376.96 inhibited the in vitro growth of chemosensitive and chemoresistant OCCs and reduced the content of CICs when used with Sunitinib. Further studies examining B7-H3 as a potential target of mAb-based immunotherapy for this type of malignancy are warranted.
University of Alabama at Birmingham, Department of Obstetrics and Gynecology, USA. Electronic address: janelle.fauci@gmail.com.
Janelle M
JM
Fauci
Massachusetts General Hospital, Harvard Medical School, Department of Surgery, USA.
Francesco
F
Sabbatino
Massachusetts General Hospital, Harvard Medical School, Department of Surgery, USA.
Yangyang
Y
Wang
University of Alabama at Birmingham, Division of Molecular and Cellular Pathology, USA.
Angelina I
AI
Londoño-Joshi
University of Alabama at Birmingham, Department of Obstetrics and Gynecology, USA.
J Michael
JM
Straughn
University of Alabama at Birmingham, Department of Obstetrics and Gynecology, USA.
Charles N
CN
Landen
Massachusetts General Hospital, Harvard Medical School, Department of Surgery, USA.
Soldano
S
Ferrone
University of Alabama at Birmingham, Department of Radiation Oncology, USA.
Donald J
DJ
Buchsbaum
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D060887:B7 Antigens / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D000939:Epitopes; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011758:Pyrroles / Q000627:therapeutic use; D000077210:Sunitinib
D000911:Antibodies, Monoclonal; D060887:B7 Antigens; C423237:CD276 protein, human; D000939:Epitopes; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib
B7-H3; Cancer initiating cells; Chemoresistance; Immunotherapy; Ovarian cancer; Sunitinib