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Eradication of large solid tumors in mice with an immunotoxin directed against tumor vasculature
1Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas 75235-8576.
Abstract:
Antibody-based therapy of solid tumors has met with limited success, chiefly because solid tumors are relatively impermeable to macromolecules. This problem could be circumvented by attacking the readily accessible endothelial cells of the tumor vascular bed. We have developed a model to test this "vascular targeting" approach in which cytokine gene transfection of the tumor cells causes them to induce an experimental marker selectively on tumor vascular endothelium. An anti-tumor endothelial cell immunotoxin caused complete occlusion of the tumor vasculature and dramatic regressions of large solid tumors. By contrast, a conventional anti-tumor cell immunotoxin of equivalent in vitro potency produced only minor, transient antitumor effects but, when combined, the two immunotoxins induced permanent complete remissions in over half of the animals. These experiments indicate that immunotoxins directed against recently described markers on vascular endothelial cells in human tumors could provide a general treatment for solid tumors in humans.
Insights
Targeting tumor blood vessels with immunotoxins offers a promising strategy for treating solid tumors. This approach, by attacking endothelial cells, achieved significant tumor regressions and complete remissions in animal models.
Area of Science:
- Oncology
- Immunotherapy
- Vascular Biology
Background:
- Solid tumors are difficult to treat with conventional antibody therapies due to their impermeability to macromolecules.
- Tumor vasculature presents an accessible target for therapeutic intervention.
Purpose of the Study:
- To evaluate the efficacy of a "vascular targeting" strategy using immunotoxins against tumor endothelial cells.
- To assess the potential of targeting tumor vasculature as a general treatment for solid tumors.
Main Methods:
- Developed a model using cytokine gene transfection to induce selective markers on tumor vascular endothelium.
- Administered anti-tumor endothelial cell immunotoxins and compared their effects with conventional anti-tumor cell immunotoxins.
- Evaluated tumor regression, vascular occlusion, and long-term remission rates in animal models.
Main Results:
- Anti-tumor endothelial cell immunotoxin treatment led to complete tumor vasculature occlusion and significant tumor regressions.
- Conventional anti-tumor cell immunotoxins showed only minor, transient effects.
- Combination therapy (anti-endothelial and anti-tumor cell immunotoxins) resulted in permanent complete remissions in over 50% of animals.
Conclusions:
- Targeting tumor vascular endothelial cells with immunotoxins is an effective strategy for treating solid tumors.
- This approach overcomes the limitations of traditional antibody therapies for solid tumors.
- Immunotoxins targeting specific markers on tumor endothelial cells hold promise for a general human solid tumor therapy.