Antiphosphatidylserine Antibody Combined with Irradiation Damages Tumor Blood Vessels and Induces Tumor Immunity in a Rat Model of Glioblastoma

Purpose: The vascular targeting antibody bavituximab is being combined with chemotherapy in clinical trials in cancer patients. Bavituximab targets the membrane phospholipid, phosphatidylserine, complexed with β2-glycoprotein I. Phosphatidylserine is normally intracellular but becomes exposed on the...

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Bibliographic Details
Published in:Clinical cancer research 2009-11, Vol.15 (22), p.6871-6880
Main Authors: He, Jin, Yin, Yi, Luster, Troy A, Watkins, Linda, Thorpe, Philip E
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - chemistry
Antibodies, Monoclonal - pharmacology
Combined Modality Therapy - methods
Dendritic Cells - cytology
Disease Models, Animal
Endothelial Cells - cytology
Glioblastoma - blood supply
Glioblastoma - immunology
Glioblastoma - radiotherapy
Glioblastoma - therapy
Glioma - pathology
Humans
immunogenicity
immunotherapy
Macrophages - metabolism
Male
malignant glioma
Monocytes - metabolism
Neovascularization, Pathologic
phosphatidylserine
Phosphatidylserines - chemistry
radiotherapy
Rats
Rats, Inbred F344
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Summary:Purpose: The vascular targeting antibody bavituximab is being combined with chemotherapy in clinical trials in cancer patients. Bavituximab targets the membrane phospholipid, phosphatidylserine, complexed with β2-glycoprotein I. Phosphatidylserine is normally intracellular but becomes exposed on the luminal surface of vascular endothelium in tumors. Phosphatidylserine exposure on tumor vessels is increased by chemotherapy and irradiation. Here, we determined whether treatment with the murine equivalent of bavituximab, 2aG4, combined with irradiation can suppress tumor growth in a rat model of glioblastoma. Experimental Design: F98 glioma cells were injected into the brains of syngeneic rats where they grow initially as a solid tumor and then infiltrate throughout the brain. Rats with established tumors were treated with 10 Gy whole brain irradiation and 2aG4. Results: Combination treatment doubled the median survival time of the rats, and 13% of animals were rendered disease free. Neither treatment given individually was as effective. We identified two mechanisms. First, irradiation induced phosphatidylserine exposure on tumor blood vessels and enhanced antibody-mediated destruction of tumor vasculature by monocytes/macrophages. Second, the antibody treatment induced immunity to F98 tumor cells, which are normally weakly immunogenic. Surviving rats were immune to rechallenge with F98 tumor cells. In vitro, 2aG4 enhanced the ability of dendritic cells (DCs) to generate F98-specific cytotoxic T cells. Phosphatidylserine exposure, which is induced on tumor cells by irradiation, likely suppresses tumor antigen presentation, and 2aG4 blocks this tolerogenic effect. Conclusion: Bavituximab combined with radiotherapy holds promise as a vascular targeting and immune enhancement strategy for the treatment of human glioblastoma. (Clin Cancer Res 2009;15(22):6871–80)
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-09-1499