Evaluation of Clostridium novyi–NT spores in dogs with naturally occurring tumors

Abstract

Objective To establish the maximum tolerated dose of Clostridium novyi–NT spores in tumor-bearing dogs and evaluate spore germination within tumors and tumor response. Animals 6 client-owned dogs. Procedures A standard dose-escalation study was planned, with maximum tolerated dose defined as the highest dose at which 0 or 1 of 6 dogs had dose-limiting toxicoses (DLT). Dogs received 1 dose of C novyi–NT spores IV. Toxicoses were graded and interventions performed according to specific guidelines. Grade 3 or higher toxicosis or any toxicosis combination that substantially affected patient status was considered DLT. Clinical response was measured by use of response evaluation criteria in solid tumors at 28 days. Results The first 2 dogs had DLT. The dose was decreased. Two of the next 4 dogs had DLT; therefore, dose administration was stopped because the study endpoint had been reached. The most common toxicosis was fever (n = 6 dogs). Two dogs developed abscesses (1 within a nasal carcinoma and 1 splenic abscess) attributable to C novyi–NT infection; both required surgical intervention. Clostridium novyi–NT was cultured from 1 of 6 tumors. Five dogs were available for response assessment (4 had stable disease; 1 had progressive disease). Conclusions and Clinical Relevance Results indicated that C novyi–NT can germinate within tumors of dogs. Toxicosis, although common and sometimes severe, was manageable with treatment. Further studies in dogs with superficial tumors may allow for continued dose escalation and provide information for use in clinical trials in veterinary and human oncology.

Role of nontoxigenic Clostridium novyi in solid tumor therapy

“…Based on the current study of its genome [38], considerable information exists about the genes controlling sporulation, germination, and growth, as well as genes affecting spore coat architecture. Similar results were observed in rabbits and dogs with certain syngeneic murine tumors [26,39]. Second, we have seen the tumoricidal ability of C. novyi-NT spores when they were injected into nude mice bearing human xenografts.…”

“…To ascertain the safety of spores of C. novyi-NT as a promising therapeutic, their potential toxicity and pharmacological characteristics were evaluated [29,39,55]. The results illuminated that no signs of clinical toxicity were observed in both healthy and tumor-bearing mice, rabbits, and dogs; in addition, clearance of the spores from circulation happened quickly after systemic injection.…”

Intratumoral injection of Clostridium novyi -NT spores induces antitumor responses

“…A single dose of intravenously injected C. novyi -NT spores into mice and rabbits bearing transplanted syngeneic tumors led to localized tumor necrosis, intense inflammatory responses, and complete responses (CRs) in 25 to 30% of the treated animals (20). On the basis of these data, intravenously injected C. novyi -NT spores were evaluated in spontaneously occurring canine tumors (21). However, at doses that exhibited acceptable toxicity, no CRs were observed.…”

Murine solid tumours as a novel model to study bacterial biofilm formation in vivo

“…In the meantime, several bacterial species have been shown to be able to invade tumours and cause growth retardation after systemic application (Table 1). These include facultative anaerobic bacteria, such as Salmonella enterica serovar Typhimurium (S. typhimurium) [3,10,11], S. choleraesuis [12] or Escherichia coli, as well as obligate anaerobic bacteria, such as Bifidobacterium longum [13] or Clostridium novyi [14,15]. In addition to a direct effect, tumour-targeting bacteria might also be used as carriers for therapeutic molecules.…”