Background:
Under the direction and sponsorship of the National Cancer Institute, we report on the first pre-clinical trial of
the Comparative Oncology Trials Consortium (COTC). The COTC is a novel infrastructure to integrate cancers that naturally
develop in pet dogs into the development path of new human drugs. Trials are designed to address questions challenging
in conventional preclinical models and early phase human trials. Large animal spontaneous cancer models can be a valuable
addition to successful studies of cancer biology and novel therapeutic drug, imaging and device development.
Methodology/Principal Findings:
Through this established infrastructure, the first trial of the COTC (COTC001) evaluated a
targeted AAV-phage vector delivering tumor necrosis factor (RGD-A-
TNF
)to
a
V integrins on tumor endothelium. Trial
progress and data was reviewed contemporaneously using a web-enabled electronic reporting system developed for the
consortium. Dose-escalation in cohorts of 3 dogs (n = 24) determined an optimal safe dose (5
6
10
12
transducing units
intravenous) of RGD-A-
TNF
. This demonstrated selective targeting of tumor-associated vasculature and sparing of normal
tissues assessed via serial biopsy of both tumor and normal tissue. Repetitive dosing in a cohort of 14 dogs, at the defined
optimal dose, was well tolerated and led to objective tumor regression in two dogs (14%), stable disease in six (43%), and
disease progression in six (43%) via Response Evaluation Criteria in Solid Tumors (RECIST).
Conclusions/Significance:
The first study of the COTC has demonstrated the utility and efficiency of the established
infrastructure to inform the development of new cancer drugs within large animal naturally occurring cancer models. The
preclinical evaluation of RGD-A-
TNF
within this network provided valuable and necessary data to complete the design of
first-in-man studies.