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REVIEW ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 8  |  Page : 1-6

Learning from Clostridium novyi-NT: How to defeat cancer


1 Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang; Research Center of Combine Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Sichuan Medical University, Luzhou, China
2 Department of Medical Affair, Chengdu Military General Hospital, Chengdu, Sichuan, China
3 Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
4 Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, China

Date of Web Publication26-Mar-2018

Correspondence Address:
Prof. Xinli Shi
Department of Immunology and Pathobiology, Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.204841

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 > Abstract 


Side effects associated with conventional anticancer therapies have prompted the new idea of solid tumor treatment strategy. One of them is using bacteria explored as potential antitumor agents over more than one century. Notably, the ideal therapy is a specifical target to tumors with limited toxicity. Here, we take “Clostridium novyi” for the search keyword in the PubMed from 2000 to 2015 and describe that C. novyi-NT spores act as “Trojan horse” for bacteriolytic therapy. This therapy is based on the fact that the live and attenuated obligate anaerobic bacteria are capable of binary fission selectively in anoxic areas of solid tumors and direct tumoricidal effects. Our succinct review mainly concentrates on the potential mechanisms of combination bacteriolytic therapy, an effective and safe tumor therapy with the help of C. novyi-NT. Importantly, C. novyi-NT spores were shown to induce solid tumor regression and exhibit the property to initiate an immune response. Therefore, C. novyi-NT spores should be an effective and safe tumor therapy.

Keywords: Anticancer agent, bacteriolytic therapy, Clostridium novyi-NT, immune response, solid tumor regression


How to cite this article:
Wang L, Wang Q, Tian X, Shi X. Learning from Clostridium novyi-NT: How to defeat cancer. J Can Res Ther 2018;14:1-6

How to cite this URL:
Wang L, Wang Q, Tian X, Shi X. Learning from Clostridium novyi-NT: How to defeat cancer. J Can Res Ther [serial online] 2018 [cited 2018 Aug 17];14:1-6. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/1/204841

Li Wang and Xiaochao Tian contributed equally to this work.





 > Introduction Top


Cancer is a major public health problem in the world.[1] To some extent, surgery, radiotherapy, and chemotherapy are effective in the treatment of solid tumors.[2] However, they often have poor selectivity and drug resistance. Live bacteria (Clostridium novyi) can overcome these limitations in solid tumors.[3],[4] Over one century, bacterial sporad was observed to cause tumor regression.[5],[6] Bacteria, the optimal robot factory, have unique capabilities such as microenvironmental sensing, motility, intratumoral targeting, nutrient competition, extracellular enzymes, immunostimulation, and genetical modification.[7] For this reason, we intensely use bacteria to treat solid tumors.


 > Cancer Strike Back of Genusclostridium Top


Recently, Swee Hin Teoh group reported that heat-inactivated Clostridium sporogenes bacteria inhibit colorectal cancer cell proliferation on a three-dimensional platform.[8] In fact, as early as the year 1813, the loading-tumor patients were reported that tumor regression by clostridial gas gangrene.[9] In 1947, spores of Clostridium histolyticum, a pathogenic strain, were directly injected into the transplanted sarcomas in mice leading to significant tumor lysis.[10] Soon after, spores of a nonpathogenic strain, Clostridium tetani, were first injected intravenously into normal and tumor-bearing mice, in which the spores did not germinate in the organs and tissues. However, all tumor-bearing mice were died with tetanus within 48 h.[11] The experiment showed that intratumoral injection was unnecessary. In 1959, spores of another nonpathogenic strain, Clostridium butyricum M-55, did not show any antitumor activity.[12] Therefore, the bacterial sporadic trials were stagnant. However, at least these studies suggested that spores of nonpathogenic strains of genus Clostridium safely germinate in the hypoxia/necrotic regions of solid tumors. Up to the year 1994, the genetically modified Clostridium beijerinckii spores as the gene delivery vector were used to target human solid tumor therapy.[13],[14]

Methods

We take “Clostridium novyi” as the search keyword in the PubMed databases for data collection. Before 2000, no study reported the tumor regression of C. novyi. Most of the research focus on the pathogenicity factors of bacteria. Therefore, only 2000–2015 studies were considered. To rule out any bias, we have reviewed all articles in 2010–2015, which have searched for the association of C. novyi and tumor regression.

The research topics of these articles

In 2001, the combination spores of a new strain, C. novyi-NT, with conventional chemotherapeutic agents resulted in a significant tumor regression, which was called combination bacteriolytic therapy (COBALT).[15] In 2002, a strain of C. butyricum genetically modified to express the deaminase,  Escherichia More Details coli enzyme cytosine, was used in the clinical studies for clostridial-dependent enzyme prodrug therapy.[16] In addition, Clostridium-directed antibody therapy is a combination of the oncolytic properties of C. novyi-NT with the target selectivity of antibody therapeutics, in which the bacteria used as carrier-expressed single-chain antibodies specific for human hypoxia-inducible factor 1 alpha, targeting the most resistant regions in human solid cancer.[17] Today, C. novyi-NT is the only Clostridium strain enrolled as an anticancer agent to investigate in human trials.[7],[18],[19],[20] Systemic injection of C. novyi-NT spores is also on the way (www.clinicaltrials.gov/ct). In 2006, Sciencereported that C. novyi enhances the release and efficacy of liposomal cancer drugs.[21] Recently, several studies have developed novel antitumor approaches using C. novyi-NT spores, such as lung neoplasms, malignant mesenchymal tumor, pancreatic cancer, soft-tissue sarcoma, stomach carcinoma, and urinary bladder neoplasms (www.clinicaltrials.gov/ct). [Table 1] lists all the cites suggested. This will provide total information for the cancer bacteria therapy related to C. novyi-NT.
Table 1: Schematic overview of candidate strains related to C. novyi-NT for cancer treatment

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 > Clostridium Novyi -Nt: from Pathogen to an Attenuated Strain Top


C. novyi is a Gram-positive spore-forming anaerobe,[22] which is a soil organism implicated in wound-associated gas gangrene.[23],[24],[25],[26] High rate C. novyi infection was reported in person who injects drugs.[27],[28]

Wild-type C. novyi is a pathogen that produces α-toxin, a lethal toxin.[24] The α-toxin is a glycosylated cellular GTPase protein, which uses UDP-GlcNAc as a sugar donor [29],[30] and targets cellular GTPase proteins leading to actin cytoskeletal disruption and cell death.[24],[31] According to the distribution in the necrotic regions when injected intravenously, the Vogelstein group selected C. novyi among 26 different strains tested, including genus Bifidobacterium, Lactobacillus, and Clostridium, and prepared the attenuated C. novyi-NTspores [Figure 1].[15] To eliminate the bacteriophage carrying the lethal a-toxin gene, C. novyi spores are heated at 70°C for 15 min.[32] The heat attenuated strain, C. novyi-NT, is generated by screening for the C. novyi-NTspores that have lost the prophage.[15] C. novyi-NThas a number of features favorable for cancer therapy. Especially, C. novyi-NT spores are easier to store, handle, and stable to nonpermissive conditions.
Figure 1: Proposed model of Clostridium novyi-NT spores eliminates solid tumors in combination bacteriolytic therapy

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Effectivity concerns

C. novyi-NT spores have been experimentally tested as an antitumor agent in animal studies and clinical trials.[19] Interestingly, dramatic tumor regressions were observed after treatment with C. novyi-NT spores and a microtubule-binding agent, dolastatin-10, or a DNA damaging agent, mitomycin C, in nude mice loading colorectal cancer cell line HCT116. The strategy was named COBALT.[15] Surprisingly, treatment with such strategy cured about 30% of mice loading tumors.[33] However, they also found that approximately 15% mortality due to tumor lysis syndrome, which was associated with the tumor size.[15]

Furthermore, combination of C. novyi-NT spores with radiation [34] or anti-vascular chemotherapeutic agents [35],[36] was subsequently determined the antitumor effect and reduced the tumor lysis syndrome. As the radio-enhancing agent, C. novyi-NT spores were used in combination with low-dose radiation, which overcome the hypoxic barriers and resulted in tumor regressions with relatively little toxicity.[34] Microtubule synthesis inhibitor resulted in slower tumor regressions than microtubule stabilizer through enlarging the hypoxic regions, in which C. novyi-NT spores germinated.[35] Accordingly, the combination of C. novyi-NT spores with a microtubule-stabilizing agent (e.g., discodermolide analogs) causes rapid and complete tumor regression in HCT116 tumor-bearing nude mice.[37]

Recently, one study provided evidence that C. novyi-NT spores result in glioblastoma, a highly aggressive primary brain tumor, localized germination, tumor destruction, and a significant survival benefit in tumor-bearing rats.[38]

Safety concerns

An ideal anticancer bacterium should be safety, effectivity, selectivity, chemotaxis, and nonimmunogenicity.[7],[39]Clostridia in the blood stream can be eliminated with the use of antibiotics such as metronidazole.[40] The genome and transcriptome of C. novyi-NT have been sequenced and determined.[41] In animal studies, systemic-administered C. novyi-NT spores have no clinical toxicity and were rapidly cleared by the reticuloendothelial system in healthy mice or rabbits.[42] Meanwhile, toxicosis induced by dose administration of C. novyi-NT spores is manageable in natural tumor-bearing dogs.[43] Today, three Phase 1 trials of COBALT about C. novyi-NT spores in patients are in progress (www.clinicaltrials.gov/ct).

In addition, C. novyi-NT can be used to evaluate the bacteriolytic therapies, in which a noninvasive magnetic resonance imaging method was developed for imaging of the distribution, accumulation, germination, and clearance of injected tumor-homing bacteria.[19],[44]


 > Proposed Mechanism Top


Tumor environmental and genetic mechanisms influence tumor angiogenesis and growth, resulting in the formation of defective blood vessels, heterogeneous blood flow, and the emergence of hypoxic/anoxic necrotic areas.[45],[46],[47] The unique solid immune-privileged tumor microenvironment, which features low oxygen and abundant nutrients,[48],[49] provides a haven for anaerobic bacteria.[50]

Systemically administered C. novyi-NT spores are distributed throughout the body but germinate only within anoxic areas of tumors.[33] Once germinated, the bacteria secrete extracellular enzymes,such as phospholipase C, proteases, and lipases, destroy adjacent cancer cells, trigger host inflammatory responses, induce antitumor immunity and tumor destruction.[21],[41],[51] At the same time, C. novyi- NT spores act as an adjuvant to stimulate immune response [Figure 1].

There are some controversy ideas about the immune-mediated mechanism. Vogelsteingroup proposed that C. novyi- NT spores act as an adjuvant to initiatethe inflammatory reaction and stimulate the CD8+ T cell-mediated cellular immune response, which can subsequently destroy residual tumor cells not lysed by the bacteria and partially protect from the same tumor rechallenge.[33] However, Maletzki et al. group showed that only injection of C. novyi-NT spores irritated the innate immune response.[52] In their study, levels of CD4+ T cells, CD8+ T cells, and B cells in the leukocytes of circulation and spleens were similar to controls. Furthermore, the protective immune memory responses to tumor and noncancer cells were nonspecific. Interestingly, the numbers of natural killer (NK) cells increased in the leukocytes of circulation and spleens. Therefore, the study reported that the bacteriolytic therapy due to the bacterium-induced NK cell-mediated innate immune response.[52] Further, the group used live Streptococcus pyogenes to treat pancreatic carcinoma and showed that not only the direct bacteriolytic activity but also the innate immune response induced by disseminated tumor components from damaged tumor cells.[53],[54]

In a word, C. novyi- NT-induced tumor regression within anoxic areas of tumors through bacteriolysis (e.g., direct competition for nutrients, localized production of extracellular enzymes), breaking the tumor-induced tolerance, and development of the immune response (e.g., inflammatory responses, innate immune, and/or adaptive immune) [Figure 2]a. The cure rate and tumor lysis syndrome of C. novyi-NT are related to the balance between bacteriolysis, angiogenesis, immune response, and tumor size [Figure 2]b.[33],[52] However, the interplay between C. novyi- NT and immune response is a complex and largely unresolved matter, which influences tumor angiogenesis and growth.
Figure 2: Working model of C. novyi-NT in tumor regression and the major problems in current therapy. (a) C. novyi-NT induced tumor regression in anoxic areas of tumors via bacteriolysis-induced immune response. (b) The cure rate and tumor lysis syndrome of C. novyi-NT are related to the balance between bacteriolysis, angiogenesis, immune response, and tumor size. (c) The major problems in current cancer bacteria therapy related to C. novyi-NT

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 > Future Perspectives Top


We are hopeful that the full potential of C. novyi-NT-mediated solid tumor regression will become clear and reality. Therefore, we show the major problems in the current therapy in [Figure 2]c. How to control the speed of tumor regression to avoid animal death or the tumor lysis syndrome in large-sized solid tumor?[15] More research is required to determine the relationship between tumor size and C. novyi-NT usage. One group proposed the pacemaker model,[55] a working hypothesis about the Clostridium proliferation within hypoxic micro-niches. Application of the hypothesis to reveal the above question in clinical trials still has a long way to go.

Owing to several unanswered questions, caution is needed. For example, it is important to learn more about the relationship between C. novyi-NT growth and the tumor cells sensing hypoxia in the solid tumor microenvironment.[56] An important direction is that C. novyi-NT was used to detect and target solid tumors. For example, staining C. novyi-NT with semiconductor nanocrystals was used as a means to detect and target neoplastic tumors.[57]


 > Conclusions Top


Modified C. novyi-NT spores acted as carrier-targeting hypoxic regions in human solid cancer.[17] In addition, C. novyi-NT secreted a novel lipase contribute to the release of liposome-encapsulated drugs within tumors.[21],[51] Especially, intratumoral injection C. novyi-NTspores prolonged survival in rats with glioma and produced an objective response in six dogs and a human patient with soft-tissue sarcomas.[58] Therefore, C. novyi- NT spores could serve as an alternative for solid tumor therapy although the precise mechanism requires further studies.

Financial support and sponsorship

This work was financially supported by the Youth Foundation of Hebei Educational Committee of China (No. QN2014012), the Research Fund for the Doctoral Program of Hebei University of Traditional Chinese Medicine (No. BSZ2015006), and the Research Fund from Hebei Key Laboratory of Integrative Medicine on Liver-kidney patterns.

Conflicts of interest

There are no conflicts of interest.



 
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