Since protection can be conferred from cured mice to naïve mice through adoptive transfer of CD8 + cells, it is likely that CNV-NT induces an immune response to the cancer cells in the inflammation following infection. This suggests that mechanisms other than isolated, direct effects of local CNV-NT infection contribute to positive outcomes, specifically, CNV-NT activates the innate immune system and primes specific anti-tumor CD8 + T cells. Adoptive transfer of CD8 + cells from mice with neoplasia cured with CNV-NT into naïve mice prevents development of induced neoplasia. In addition, after CNV-NT spore treatment, animals are protected against challenge with the same tumor cell line. Oxygenated tissue regions near the outer rim of the tumor often remain unaltered by the local effects of CNV-NT, yet there is a 30% cure rate in CNV-NT spore treated mice. After germination, CNV-NT secretes hydrolytic proteases and lipases which results in destruction of cancer cells and tumor regression in hypoxic regions. However, it is possible that this dog had an undetected metastatic lesion in the spleen that was the hypoxic focus of germination. The exception to this is a report of a splenic abscess in a dog post-CNV-NT administration intravenously. However, CNV-NT maintains obligate anaerobic properties making it an ideal candidate bacteriolytic therapy for hypoxic solid tumors.ĬNV-NT germinates in hypoxic regions of tumors yet does not germinate in other hypoxic regions including myocardial infarction. This bacterium lacks the gene for the alpha-toxin.
novyi wild type by heat treating the bacterial phage that carries the alpha toxin and serial passaging.
Alpha-toxin results in severe, painful edema which can progress to necrosis, refractory hypotension, leukocytosis, and visceral effusions. Alpha-toxin is one of the virulence factors produced by C. CNV-NT typically causes pathological conditions through a combination of toxin release and the resulting inflammatory reaction. Ĭlostridium novyi is an obligate anaerobic, spore forming bacterium found predominately in the soil that is associated with gas gangrene. Clostridium novyi-NT (CNV-NT) spore immunotherapy has successfully cured induced neoplasia in mouse models and resulted in objective tumor responses in naturally developing neoplasia in the dog. In more modern times, the controlled use of bacteriolytic immunotherapy has been evaluated in both induced and spontaneous tumor models.
Future investigations evaluating long-term immune system changes and associations between immune function and tumor remission rates should include evaluation of these pathways.įor centuries it has been recognized that certain bacterial infections could induce tumor regression. Increased NK cell-like function was sustained to 28 (intratumoral) or 56 (intravenous) days post-treatment, and increased phagocytic function was sustained to 28 days post-treatment suggesting that CNV-NT spores induce longer-term immune cell function changes.
Intravenous injection of CNV-NT spores resulted in increased LPS-induced TNF-α production, LTA-induced IL-10 production and NK cell-like function post-treatment. Intratumoral injection of CNV-NT spores result in increased phagocytosis and NK cell-like function after treatment. The objective of this pilot, descriptive, prospective, clinical investigation, was to evaluate and describe the immune response to CNV-NT spores to better understand which immune pathways might play a role in the response to this bacteriolytic immunotherapy. Clostridium novyi-NT (CVN-NT) spores germinate in hypoxic regions of tumors and have successfully cured induced neoplasia in mouse models and resulted in objective tumor responses in naturally developing neoplasia in the dog.