Intratumoral injection of Clostridium novyi -NT spores induces antitumor responses

Abstract

Species of Clostridium bacteria are notable for their ability to lyse tumor cells growing in hypoxic environments. We show that an attenuated strain of Clostridium novyi (C. novyi-NT) induces a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model after intratumoral injection. It is well known, however, that experimental models often do not reliably predict the responses of human patients to therapeutic agents. We therefore used naturally occurring canine tumors as a translational bridge to human trials. Canine tumors are more like those of humans because they occur in animals with heterogeneous genetic backgrounds, are of host origin, and are due to spontaneous rather than engineered mutations. We found that intratumoral injection of C. novyi-NT spores was well tolerated in companion dogs bearing spontaneous solid tumors, with the most common toxicities being the expected symptoms associated with bacterial infections. Objective responses were observed in 6 of 16 dogs (37.5%), with three complete and three partial responses. On the basis of these encouraging results, we treated a human patient who had an advanced leiomyosarcoma with an intratumoral injection of C. novyi-NT spores. This treatment reduced the tumor within and surrounding the bone. Together, these results show that C. novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted.

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

“…Live Salmonella (ClinicalTrials.gov Identifier NCT01099631), Listeria (ClinicalTrials.gov Identifier NCT01598792; ClinicalTrials.gov Identifier NCT01675765; ClinicalTrials.gov Identifier NCT02002182), and Clostridium (ClinicalTrials.gov Identifier NCT01118819) all have current or recent FDA-sanctioned human clinical studies in the cancer treatment setting. 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).…”

“…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.…”

Germinants and Their Receptors in Clostridia

“…Clostridium novyi, a soil-dwelling organism incriminated in wound associated gangrene and infections in intravenous (i.v.) drug users (19), was shown to be important in treating tumors (20)(21)(22)(23). Moreover, Clostridium bifermentans subsp.…”

Cancer in North Cyprus: 2. Biomedical Research Activities

“…Bacterial endotoxins (Lipopolysaccharides) and immune-toxins can be used for both destruction of tumor tissue and development of vaccines (26). Bacteria can also be used as vectors for gene therapy and/or administration of anticancer products (27). Spores of anaerobic bacteria can reach and germinate only in oxygen-poor tumor regions and become activated.…”

“…For example, cytosine deaminase (converting 5-fluorocytosine to 5-fluorouacil) and nitroreductase (transforming CB1954 prodrug to a DNA crosslinking agent) have been utilized in in vitro cancer models using Clostridium sporogenes as a vector and have been shown to kill tumor cells (33). Similarly, another study showed that intratumoral injection of an attenuated strain of C. novyi reduced tumor volume in several preclinical animal models as well as in one phase I study on a human with metastatic disease (27). Salmonella has also been used as a vector in this case for cytosine deaminase and nitroreductase which exhibited anti-cancer effects in vivo (28).…”