Systemic Administration of an Attenuated, Tumor-TargetingSalmonella typhimuriumto Dogs with Spontaneous Neoplasia: Phase I Evaluation

Abstract

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 × 105 to 1 × 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 × 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 VNP20009 at doses with acceptable toxicity results in detectable bacterial colonization of tumor tissue and significant antitumor activity in tumor-bearing dogs.

EGFR‐targeted Chimeras of Pseudomonas ToxA released into the extracellular milieu by attenuated Salmonella selectively kill tumor cells

“…Results of the Clostridium trial have recently been published (Roberts et al, 2014) and demonstrated an anti-tumor response. The preclinical studies of Clostridium also showed antitumor activity in a veterinary trial with pet dogs (Roberts et al, 2014) and an earlier study using Salmonella VNP20009 also showed significant antitumor activity in dogs with spontaneous neoplasms (Thamm et al, 2005). Continued success is likely to sustain interest in these novel therapeutic approaches.…”

“…However, in a human clinical study of lipid-modified Salmonella strain VNP20009 on patients with melanoma (ClinicalTrials.gov Identifier NCT00004988; Toso et al, 2002), there was no antitumor activity, even in patients that were confirmed to have the bacteria in their tumors. Despite the lack of success in humans, VNP20009 was shown to be effective against spontaneous neoplasms in dogs, including four complete responses and an overall response rate of 42% (Thamm et al, 2005). …”

Outcome and Prognostic Factors Following Adjuvant Prednisone/Vinblastine Chemotherapy for High-Risk Canine Mast Cell Tumour: 61 Cases

“…Twenty patients received additional therapy after having failed prednisone/VBL, including surgery (n=12), RT (n=3), and medical therapy (n=12) (additional prednisone/ VBL, asparaginase, lomustine, vinorelbine, prednisone alone, dolastatin-10 [27] or genetically modified Salmonella [26]). Several dogs received more than one additional form of treatment.…”

AttenuatedSalmonellaengineered to produce human cytokine LIGHT inhibit tumor growth

“…Humans are not a natural host for S. typhimurium, and the elimination of lipid A prevents production of endotoxin (lipopolysaccharide), making these microorganisms nonvirulent. Because they have an acceptable safety profile (5,8) and are able to synthesize recombinant cytokines at high levels (9), we chose these bacteria for our studies, with a goal to explore the preclinical antitumor activity of S. typhimurium engineered to secrete cytokines. With the ability to grow anaerobically, we reasoned that S. typhimurium could grow even in hypoxic areas of tumors, which tend to be resistant to radiation or chemotherapy.…”