Launching a Novel Preclinical Infrastructure: Comparative Oncology Trials Consortium Directed Therapeutic Targeting of TNFα to Cancer VasculatureReportar como inadecuado




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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 αV 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 5×1012 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.



Autor: Melissa C. Paoloni , Anita Tandle , Christina Mazcko, Engy Hanna, Stefan Kachala, Amy LeBlanc, Shelley Newman, David Vail, Caroly

Fuente: http://plos.srce.hr/



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