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Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from
James P B O'Connor1, Richard A D Carano, Andrew R Clamp
1Imaging Science and Biomedical Engineering, School of Cancer and Imaging Sciences, University of Manchester, Manchester, United Kingdom. james.o'connor@manchester.ac.uk
Purpose:
Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti-vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials.
Experimental Design:
Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab.
Results:
Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P
Conclusion:
These data suggest that VEGF-specific inhibition induces rapid structural and functional effects with downstream significant antitumor activity within one cycle of therapy. This finding has important implications for the design of early-phase clinical trials that incorporate physiologic imaging. The study shows how animal data help interpret clinical imaging data, an important step toward the validation of image biomarkers of tumor structure and function.
Insights
Anti-vascular endothelial growth factor (VEGF) therapies rapidly reduce tumor blood vessels and volume within 48 hours. These early structural and functional changes correlate with significant antitumor activity, guiding clinical trial design.
Area of Science:
- Oncology
- Medical Imaging
- Pharmacology
Background:
- Limited understanding of anti-VEGF therapy effects on tumor vasculature.
- Need for knowledge to guide therapeutic development and optimize imaging in early clinical trials.
Purpose of the Study:
- To investigate the onset, duration, and magnitude of direct therapeutic effects of anti-VEGF therapies.
- To guide rational development of targeted therapeutics and optimize imaging technologies in early-phase clinical trials.
Main Methods:
- Preclinical studies utilized ex vivo microcomputed tomography and in vivo ultrasound imaging in a colorectal xenograft model treated with anti-VEGF antibody G6-31.
- Clinical evaluation involved quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab.
Main Results:
- Preclinical imaging showed reduced perfused vessels and tumor blood volume within 24-48 hours of anti-VEGF administration.
- Clinical imaging revealed decreased enhancing fraction and plasma volume within 48 hours of bevacizumab, persisting for one cycle.
- Therapy led to edema resolution and tumor shrinkage in a subset of patients.
Conclusions:
- VEGF inhibition rapidly induces structural and functional changes with significant antitumor activity within one therapy cycle.
- Findings have implications for designing early-phase clinical trials incorporating physiologic imaging.
- Animal data aids in interpreting clinical imaging, supporting validation of image biomarkers for tumor structure and function.
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