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Antiangiogenic Drugs Synergize with a Membrane Macrophage Colony-Stimulating Factor-Based Tumor Vaccine to Therapeutically Treat Rats with an Established Malignant Intracranial Glioma¹

Edward W. B. Jeffes, Jian Gang Zhang^*, Neil Hoa^*, Animesh Petkar^*, Christina Delgado^*, Samuel Chong, Andre Obenaus, Ramon Sanchez^*, Sakineh Khalaghizadeh^*, Tetyana Khomenko^*, Brandon A. Knight^*, Reza Alipanah^*, Tuong-Vi Nguyen^*, Chirag Shah^*, Seema Vohra^*, Jing-Li Zhuang^*, Jessie Liu^*, H. Terry Wepsic^* and Martin R. Jadus^2,*

^* Diagnostic and Molecular Health Care Group, Veterans Affairs Medical Center, Long Beach, CA 90822, and Pathology Department, University of California, Irvine, CA 92117; Dermatology Service, Veterans Affairs Medical Center, Long Beach, CA 90822, and Department of Dermatology, University of California, Irvine, CA 92117; and Non-Invasive Imaging Laboratory, Radiobiology Program, Loma Linda University, Loma Linda, CA 92324

Combining a T9/9L glioma vaccine, expressing the membrane form of M-CSF, with a systemic antiangiogenic drug-based therapy theoretically targeted toward growth factor receptors within the tumor’s vasculature successfully treated >90% of the rats bearing 7-day-old intracranial T9/9L gliomas. The antiangiogenic drugs included (Z)-3-[4-(dimethylamino)benzylidenyl]indolin-2-one (a platelet-derived growth factor receptor and a fibroblast growth factor receptor 1 kinase inhibitor) and oxindole (a vascular endothelial growth factor receptor 2 kinase inhibitor). A total of 20–40% of the animals treated with the antiangiogenic drugs alone survived, while all nontreated controls and tumor vaccine-treated rats died within 40 days. In vitro, these drugs inhibited endothelial cells from proliferating in response to the angiogenic factors produced by T9/9L glioma cells and prevented endothelial cell tubulogenesis. FITC-labeled tomato lectin staining demonstrated fewer and constricted blood vessels within the intracranial tumor after drug therapy. Magnetic resonance imaging demonstrated that the intracranial T9 glioma grew much slower in the presence of these antiangiogenic drugs. These drugs did not affect in vitro glioma cell growth nor T cell mitogenesis. Histological analysis revealed that the tumor destruction occurred at the margins of the tumor, where there was a heavy lymphocytic infiltrate. Real-time PCR showed more IL-2-specific mRNA was present within the gliomas in the vaccinated rats treated with the drugs. Animals that rejected the established T9/9L glioma by the combination therapy proved immune against an intracranial rechallenge by T9/9L glioma, but showed no resistance to an unrelated MADB106 breast cancer.

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The JI 2005 174: 2447-2449. [Full Text]  

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