Launching a novel preclinical infrastructure: Comparative oncology trials consortium directed therapeutic targeting of TNFα to cancer vasculature

Melissa C. Paoloni, Anita Tandle, Christina Mazcko, Engy Hanna, Stefan Kachala, Amy LeBlanc, Shelley Newman, David Vail, Carolyn Henry, Douglas Thamm, Karin Sorenmo, Amin Hajitou, Renata Pasqualini, Wadih Arap, Chand Khanna, Steven K. Libutti

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere4972
JournalPLoS One
Volume4
Issue number3
DOIs
StatePublished - Mar 30 2009
Externally publishedYes

Fingerprint

Oncology
Launching
infrastructure
Tumors
therapeutics
neoplasms
Neoplasms
Animals
Dogs
Pharmaceutical Preparations
Tissue
Therapeutics
Bacteriophages
Biopsy
dogs
Integrins
drugs
phage vectors
dosage
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Launching a novel preclinical infrastructure : Comparative oncology trials consortium directed therapeutic targeting of TNFα to cancer vasculature. / Paoloni, Melissa C.; Tandle, Anita; Mazcko, Christina; Hanna, Engy; Kachala, Stefan; LeBlanc, Amy; Newman, Shelley; Vail, David; Henry, Carolyn; Thamm, Douglas; Sorenmo, Karin; Hajitou, Amin; Pasqualini, Renata; Arap, Wadih; Khanna, Chand; Libutti, Steven K.

In: PLoS One, Vol. 4, No. 3, e4972, 30.03.2009.

Research output: Contribution to journalArticle

Paoloni, MC, Tandle, A, Mazcko, C, Hanna, E, Kachala, S, LeBlanc, A, Newman, S, Vail, D, Henry, C, Thamm, D, Sorenmo, K, Hajitou, A, Pasqualini, R, Arap, W, Khanna, C & Libutti, SK 2009, 'Launching a novel preclinical infrastructure: Comparative oncology trials consortium directed therapeutic targeting of TNFα to cancer vasculature', PLoS One, vol. 4, no. 3, e4972. https://doi.org/10.1371/journal.pone.0004972
Paoloni, Melissa C. ; Tandle, Anita ; Mazcko, Christina ; Hanna, Engy ; Kachala, Stefan ; LeBlanc, Amy ; Newman, Shelley ; Vail, David ; Henry, Carolyn ; Thamm, Douglas ; Sorenmo, Karin ; Hajitou, Amin ; Pasqualini, Renata ; Arap, Wadih ; Khanna, Chand ; Libutti, Steven K. / Launching a novel preclinical infrastructure : Comparative oncology trials consortium directed therapeutic targeting of TNFα to cancer vasculature. In: PLoS One. 2009 ; Vol. 4, No. 3.
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abstract = "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.",
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AU - Hanna, Engy

AU - Kachala, Stefan

AU - LeBlanc, Amy

AU - Newman, Shelley

AU - Vail, David

AU - Henry, Carolyn

AU - Thamm, Douglas

AU - Sorenmo, Karin

AU - Hajitou, Amin

AU - Pasqualini, Renata

AU - Arap, Wadih

AU - Khanna, Chand

AU - Libutti, Steven K.

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