Antiphosphatidylserine antibody combined with irradiation damages tumor blood vessels and induces tumor immunity in a rat model of glioblastoma

Jin He, Yi Yin, Troy A. Luster, Linda Watkins, Philip E. Thorpe

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)6871-6880
Number of pages10
JournalClinical Cancer Research
Volume15
Issue number22
DOIs
StatePublished - Nov 15 2009

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Vascular Tissue Neoplasms
Glioblastoma
Immunity
Antibodies
Phosphatidylserines
Neoplasms
Blood Vessels
Brain
Therapeutics
Drug Therapy
Vascular Endothelium
Antigen Presentation
Neoplasm Antigens
Glioma
Dendritic Cells
Monocytes
Phospholipids
Glycoproteins
Research Design
Radiotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Antiphosphatidylserine antibody combined with irradiation damages tumor blood vessels and induces tumor immunity in a rat model of glioblastoma. / He, Jin; Yin, Yi; Luster, Troy A.; Watkins, Linda; Thorpe, Philip E.

In: Clinical Cancer Research, Vol. 15, No. 22, 15.11.2009, p. 6871-6880.

Research output: Contribution to journalArticle

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