Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging.
OBJECTIVE
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.


METHODS
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 <or= 0.005). Ultrasound imaging confirmed reduced tumor blood volume within the same time frame (P = 0.048). Consistent with the preclinical results, reductions in enhancing fraction and fractional plasma volume were detected in patient colorectal cancer metastases within 48 h after a single dose of bevacizumab that persisted throughout one cycle of therapy. These effects were followed by resolution of edema (P = 0.0023) and tumor shrinkage in 9 of 26 tumors at day 12.


CONCLUSIONS
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.
O'Connor
James P B
JP
Imaging Science and Biomedical Engineering, School of Cancer and Imaging Sciences, University of Manchester, Manchester, United Kingdom. james.o'connor@manchester.ac.uk
Carano
Richard A D
RA
Clamp
Andrew R
AR
Ross
Jed
J
Ho
Calvin C K
CC
Jackson
Alan
A
Parker
Geoff J M
GJ
Rose
Chris J
CJ
Peale
Franklin V
FV
Friesenhahn
Michel
M
Mitchell
Claire L
CL
Watson
Yvonne
Y
Roberts
Caleb
C
Hope
Lynn
L
Cheung
Sue
S
Reslan
Hani Bou
HB
Go
Mary Ann T
MA
Pacheco
Glenn J
GJ
Wu
Xiumin
X
Cao
Tim C
TC
Ross
Sarajane
S
Buonaccorsi
Giovanni A
GA
Davies
Karen
K
Hasan
Jurjees
J
Thornton
Paula
P
del Puerto
Olivia
O
Ferrara
Napoleone
N
van Bruggen
Nicholas
N
Jayson
Gordon C
GC
D000293:Adolescent; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D003952:Diagnostic Imaging; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab