Abstract
The vasculature of mouse breast tumor spheroids grown on mammary fat pad tissue in an intravital microscopy (IVM) viewing chamber was shown to derive from infiltrating angiogenic mammary vessels. The receptors tissue factor (TF), α V β 3 integrin and Tie-2 were expressed on the vascular endothelium in the periphery but not in the center of the tumor spheroids nor in the mammary tissue nor in smooth muscle tissue, whereas Tie-1 and PCAM-1 were expressed extensively in the entire tumor and in the vascular endothelium of the entire tumor nodule and in normal mammary tissue. TF is a specific target for adenoviral vector-mediated cancer immunotherapy. Subcutaneous injection of the AdfVII/IgG1Fc vector leads to the release into the system circulation of a fVII/IgG1Fc immunoconjugate molecule that binds specifically and tightly to TF on vascular endothelial cells and tumor cells, activating a cytolytic immune response against the targeted cells. We show that a single administration of the AdfVII/IgG1Fc vector destroys the peripheral but not the central vasculature of a tumor spheroid, causing partial tumor regression; additional administrations prevent regeneration of the peripheral vasculature and regrowth of the tumor. These findings indicate that a critical parameter for optimizing tumor damage is the schedule for successive administrations of the AdfVII/IgG1Fc, which should coincide with the regeneration of the peripheral vasculature and continue until the tumor is destroyed.
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Acknowledgements
We recognize the support of the NIH (R21CA096232-01, and PPG CA 104898-01), the Sidney Kimmel Foundation and the DOD (PC 01-0239). ZH acknowledges support from the Swebilius Translational Cancer Research Award from Yale Cancer Center. We also recognize contributions of the Schutz Polis Foundation, the Brian Schultz Foundation, The Anthony Dewitt Frost Fund, the George and Barbara Bush Leukemia Research Fund and Sidney Kimmel.
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Tang, Y., Borgstrom, P., Maynard, J. et al. Mapping of angiogenic markers for targeting of vectors to tumor vascular endothelial cells. Cancer Gene Ther 14, 346–353 (2007). https://doi.org/10.1038/sj.cgt.7701030
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DOI: https://doi.org/10.1038/sj.cgt.7701030
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