Intratumoral injection of bacteria destroys tumors

The oxygen concentration in solid tumors is always lower than that in normal tissues. The hypoxic areas of tumors offer a perfect ground for the growth of anaerobic bacteria. A new study from BioMed Valley Discoveries has shown that intratumoural injection of an attenuated version of Clostridium novyi (诺维氏芽孢梭菌) can shrink tumors in rats, dogs, and a human patient[1].

The original idea of using bacteria to combat cancer comes from William Coley who treated tumors by repeated inoculations of erysipelas (丹毒)[2]. Concerning the unacceptable toxicity of pathogenic bacteria, scientists developed attenuated strains of Salmonella typhimurium (鼠伤寒沙门氏杆菌) and others. However, none of the patients experienced objective tumor regression in a phase I study[3].

Over a decade ago, Bert Vogelstein tested 26 different strains and identified a particularly promising one called Clostridium novyi[4]. An attenuated strain called C. novyi-NT was generated by deleting the lethal toxin gene. This kind of bacteria is highly sensitive to oxygen whereas its spores are resistant to oxygen. Moreover, C. novyi-NT doesn’t generate spores in non-tumor tissue. As such, vegetative C. novyi-NT is not viable outside the hypoxic tumor microenvironment.

Though intravenous injection of C. novyi-NT resulted in complete responses in 25-33% of the treated mice and rabbits bearing transplanted syngeneic tumors[5], no complete responses were seen in dogs with naturally occurring cancers[6].

Saurabh Saha and his colleagues hypothesized that injecting the spores directly into tumors might have advantages over intravenous injection. Of sixteen dogs treated, three complete and three partial responses were observed. On the basis of these results, the authors tested C. novyi-NT in a woman with heavily pretreated retroperitoneal leiomyosarcoma (腹膜后平滑肌肉瘤). On day 29, a follow-up MRI demonstrated a significant amount of tumor had been destroyed.

Because C. novyi-NT is exquisitely sensitive to oxygen, it would theoretically not work in normoxic areas of tumors. The authors suggested that the bacteria may induce immune responses which contribute to the complete responses observed in dogs.

By the way, an open-label phase I study of a single intratumoral injection of C. novyi-NT spores (NCT01924689) is currently on-going in patients with treatment-refractory solid tumors. The bacteria could give hope to inoperable patients who haven’t any other options.

[1] Sci Transl Med. 2014, 6(249), 249ra111.

[2] Clin Orthop Relat Res. 1991, (262), 3-11.

[3] J Clin Oncol. 2002, 20(1), 142-152.

[4] Proc Natl Acad Sci U S A. 2001, 98(26), 15155-15160.

[5] Proc Natl Acad Sci U S A. 2004, 101(42), 15172-15177.

[6] Am J Vet Res. 2012, 73(1), 112-118.

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