Intratumoural injections of bacteria result in oncolysis of solid tumours, first-in-man study shows

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The results were presented at the seventh annual Symposium on Clinical Interventional Oncology (CIO, 31 January–5 February, Hollywood, USA), in collaboration with the International Symposium on Endovascular Therapy (ISET, 31 January–5 February, Hollywood, USA) by Ravi Murthy, Department of Interventional Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, USA.

Providing some background, Murthy explained that hypoxic environments, as those that occur in tumours, are favourable for Clostridium subspecies to germinate. “C novyi-NT induces a microscopic and tumour-confined lysis after intratumoural injection in rat orthotopic brain tumour models and spontaneous solid tumours in dogs, with the commonest toxicity being the symptoms accompanying a bacterial infection.

 

“When tumours reach a certain size, parts of them do not receive oxygen, which makes them resistant to conventional therapies such as radiation and chemotherapy,” said Murthy. “C novyi-NT thrives under these conditions, hones in on the low-oxygen areas and destroys tumours from the inside while sparing normal tissue.”

The researchers are conducting a first-in-man phase I study selecting therapy refractory solid tumours palpable, or identifiable under imaging guidance and amenable to percutaneous injection of C novyi-NT spores.

“Tumour environment hypoxia is dynamic, spatially heterogenic, and not evaluable using clinical imaging technology, thereby rendering localisation of the optimal intratumoural injection location for spore inoculation impossible. In order to compensate for this unknown parameter, we employed a staged, multifocal intratumoural delivery process to theoretically increase the likelihood of spore deposition within a milieu conducive for germination,” he said. 

The team is enrolling advanced solid tumour cancer patients with at least one injectable tumour >1cm in five dose-escalating cohorts to receive single 3cc intratumoural injections of 1E4, 3E4, 1E5, 3E5, or 1E6 C novyi-NT spores.

They injected the C. novyi-NT spores through the skin under radiographic guidance into tumours in six people. Growth of C. novyi was confirmed when computed tomography (CT) and magnetic resonance imaging (MRI) scans of the treated tumours showed gas pockets and evidence of necrosis, or cell death. Fever and elevated white blood cell count provided further evidence that the bacteria were growing and destroying cancer cells.

Six patients have been treated to date. Five are alive and one died from unrelated causes after seven months.  “Two patients demonstrated clinical evidence of germination within 72 hours corroborated by imaging and pathology confirmed oncolysis. The liquefied components of the tumour were managed with evacuation via percutaneous drainage and pre-specified protocol mandated multi-antimicrobial therapy,” Murthy said.

Once inside the tumour, the C. novyi-NT spores germinate, kill tumour cells and then feast on the waste. C. novyi-NT bacteria stop growing and die when exposed to oxygen which is abundant in healthy tissue. C. novyi-NT also is known to provoke an immune response against the cancer.

“Essentially, C. novyi-NT causes a potent cancer killing infection in the tumour,” said principal investigator Filip Janku, associate professor, Department of Investigation Therapeutics, MD Anderson Cancer Center.

Murthy and colleagues have previously used naturally occurring canine tumours as a translational bridge to human trials as reported in the journal Science Translational Medicine in August 2014. “Canine tumours 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 intratumoural injection of C novyi-NT spores was well-tolerated in companion dogs bearing spontaneous solid tumours, 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.