Systemic administration of an attenuated, tumor-targeting Salmonella typhimurium to dogs with spontaneous neoplasia: phase I evaluation.
OBJECTIVE
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.


METHODS
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 10(5) to 1 x 10(8) 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 10(7) 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 VNP20009 at doses with acceptable toxicity results in detectable bacterial colonization of tumor tissue and significant antitumor activity in tumor-bearing dogs.
Department of Medical Sciences and Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, USA. dthamm@colostate.edu
Douglas H
DH
Thamm
Ilene D
ID
Kurzman
Ivan
I
King
Zujin
Z
Li
Mario
M
Sznol
Richard R
RR
Dubielzig
David M
DM
Vail
E Gregory
EG
MacEwen
D000818:Animals; D001428:Bacterial Vaccines; D003967:Diarrhea / Q000139:chemically induced; D004283:Dog Diseases / Q000188:drug therapy / Q000276:immunology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005334:Fever / Q000139:chemically induced; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000662:veterinary; D012486:Salmonella typhimurium / Q000276:immunology; D016896:Treatment Outcome; D014613:Vaccines, Attenuated / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D014839:Vomiting / Q000139:chemically induced
D001428:Bacterial Vaccines; C465023:VNP 20009; D014613:Vaccines, Attenuated