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Systemic Administration of an Attenuated, Tumor-Targeting Salmonella typhimurium to Dogs with Spontaneous Neoplasia: Phase I Evaluation

Authors' Affiliations: Departments of ¹ Medical Sciences and ² Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, ³ University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin, and ⁴ Vion Pharmaceuticals, Inc., New Haven, Connecticut

Requests for reprints: Douglas H. Thamm, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 300 West Drake Road, Fort Collins, CO 80523. Phone: 970-297-4075; Fax: 970-297-1254; E-mail: dthamm{at}colostate.edu.

Purpose: Genetically modified bacteria are a potentially powerful anticancer therapy due to their tumor targeting capacity, inherent antitumor activity, and ability to serve as efficient vectors for gene delivery. This study sought to characterize the acute and short-term toxicities and tumor colonization rates of a genetically modified Salmonella typhimurium (VNP20009 in dogs with spontaneous tumors, in the context of a phase I dose escalation trial.

Experimental Design: Forty-one pet dogs with a variety of malignant tumors received weekly or biweekly i.v. infusions of VNP20009 at doses ranging from 1.5 x 10⁵ to 1 x 10⁸ cfu/kg. Vital signs and clinicopathologic variables were monitored regularly. Incisional biopsies were obtained before and 1 week following the first infusion for histopathology and bacterial culture.

Results: The nominal maximum tolerated dose was 3 x 10⁷ cfu/kg, with refractory fever and vomiting being the dose-limiting toxicities. One treatment-related acute death occurred. Bacteria were cultured from tumor tissue in 42% of cases. Thirty-five patients were evaluable for antitumor response. Major antitumor responses were seen in 15% (4 complete response and 2 partial response), and disease stabilization for at least 6 weeks in 10%.

Conclusions: Administration of VNP20009at doses with acceptable toxicity results in detectable bacterial colonization of tumor tissue and significant antitumor activity in tumor-bearing dogs.

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