Keywords: Bacillus Calmette-Guérin vaccine, cancer,Clostridium spp., Coley’s toxin, microorganisms, spontaneous regression, treatment

Historical aspects of spontaneous regression of tumour

As mentioned above, the origin of cancer therapy, associated with spontaneous regression, can be traced back to the time when people did not have any idea about the existence of microorganisms or their potential therapeutic effects in the treatment of tumours.

The first evidence for treatment for cancer comprising microorganisms was seen in the Iberian papyrus (1550 BC). The Egyptian pharaoh Imhotep (2600 BC) used poultice, followed by incision, for the treatment of tumour. This would facilitate the development of infection in the desired location and would cause regression of the tumour. During the 17th and 18th centuries, various forms of immunotherapy in cancer became widespread2,6,8.

The phenomenon of spontaneous regression is also well-known as St. Peregrine tumour. Peregrine Laziozi was afflicted by cancer of the tibia that required a leg amputation. The tumour progressed until the skin was impaired and the tumour was seriously infected. Subsequently, to the astonishment of the physician, the tumour was no longer present. The relapse of cancer was not observed2,8.

In the 18th and 19th centuries, septic dressings enclosing ulcerative tumours were used for the treatment of cancer. Surgical wounds were left open to facilitate the development of infection, and purulent sores were created deliberately9.

In 1813, Vautier reported regression of cancer in patients with gangrene, and in such individuals, the tumour was found to be infected withClostridium spp. Later, it was shown that the causative agent was the bacterium,Clostridium perfringens10,11.

Another important mention concerning the interconnection between infectious diseases and spontaneous regression of cancer is Dupuytren’s publication in 1829. It describes the case of a woman with progressive breast cancer who refused surgery. Eighteen months later, the health status of the woman worsened significantly, and she was bedridden, cachectic, and almost moribund. Febrile illness and vomiting followed closely and the tumour was inflamed and gangrenous. Three incisions were made by the physician into the tumour to remove a large amount of viscous fluid. Within 8 days, the cancer had regressed to a third of its original size. Within 4 weeks, no clinical symptom of the tumour was present9.

Busch in the year 1868 was treating a patient with incurable cancer. After the first cauterization of the tumour on her neck, he assigned the patient the bed next to another patient suffering from an infectious skin disease, erysipelas [causative agentStreptococcus (Str.)pyogenes]. The woman with the tumour became ill withStreptococcus spp. infection, and subsequently rapid tumour regression was observed. The same idea was also proposed by Fehleisen in 18824,10.

One of the most well-known effects of microorganisms on the spontaneous regression of cancer was reported in 1891, when an American surgeon, William B. Coley, inoculated patients having inoperable tumours withStr. pyogenes. Unfortunately, the results were not as effective as expected, and a wide range of side effects were observed10. Despite this limitation, 51.9% of the patients with inoperable soft-tissue sarcomas showed complete tumour regression and survived for more than 5 years, and 21.2% of the patients had no clinical evidence of tumour at least 20 years after this treatment5. To eliminate these side effects, Coley developed a toxin that contained heat-killed bacteria,Str. pyogenes andSerratia (Ser.)marcescens. Until 1963, this treatment was used for the treatment of sarcomas2,10. We have dedicated a whole section of this review to the usage of Coley’s toxin.

The most promising clinical application of microbial agents in the treatment of cancer was discovered in 1976, when Morales, Eidinger and Bruce published on the successful treatment of superficial urinary bladder cancer after inoculation with Bacillus Calmette-Guérin (BCG) vaccine, which is the standard vaccine against tuberculosis. Today, this therapeutic approach has become the method of choice for high-risk urinary bladder tumours10,12.

Microorganisms and spontaneous regression of tumour

As mentioned above, the role of microorganisms in spontaneous regression of malignancy has been known and studied for a long time. Scientists have tried to define the criteria that allow a microorganism to become an ‘ideal’ tool for cancer therapy.

These criteria are as follows: it should be nontoxic to the host, it should replicate only in the tumour and it should be mobile and capable of spreading the cancer (in hypoxic and necrotic regions). In addition, it should be slowly and completely removable from the macroorganism, it should be nonimmunogenic and it should be capable of lysing tumour cells13.

Coley’s toxin

More than 100 years ago, in 1891, an American surgeon William B. Coley observed that application of suitable microorganisms could significantly affect subsequent tumour progression3,14,15. Cancer patients were treated by injection with the so-called Coley’s toxin, which contained heat-killed microorganisms –Str. pyogenes andSer. marcescens1,3,5. Coley’s toxin was often used for the successful treatment of sarcomas, carcinomas, lymphomas, melanomas and myelomas. Complete and prolonged regression of advanced stages of malignant disease was documented in many cases. The author has previously reported that in 80% of the cases of malignant tumours, for which no alternate form of treatment was available, survival was longer than 5 years. Even in end-stage cancer patients, notable improvements in health were described7,16. During treatment with Coley’s toxin, a broad spectrum of side effects of the administered adjuvant occur, owing to which this treatment is not generally accepted among clinicians3.

Coley set the basic steps for the successful administration of the toxin. After the application, infection with resulting fever should develop. Immunotolerance is induced by a gradual increase in the toxin dose (dependent on the immune response of the patient). Wherever possible, the toxin should be injected directly into the tumour or at the site to which it has metastasized. The injection should be administered daily or every other day for a period of 1–2 months and then once a week for at least 6 months to prevent recurrence of the disease2,7,8.

An interesting phenomenon that occurred during treatment with Coley’s toxin was that the fever moderated the pain in cancer patients. This finding has been previously described in other studies as well. As a result, some patients could reduce the use of painkillers. This effect was often described immediately after the injection. Hoption Cann8 has described Lagueux’s observation that the pain always disappeared after the first injection.

Coley emphasized that induction of fever was the most important symptom for inducing spontaneous regression of cancer. In a retrospective study of patients with inoperable sarcoma after treatment with Coley’s toxin, a greater than 5-year survival rate was reported among those who had high fever (38–40°C), compared to those who had no fever or only slightly elevated temperature during the treatment2.

It is assumed that the main factor responsible for the therapeutic effect of Coley’s toxin was the increased expression of tumour necrosis factor (TNF), interleukins (ILs) and interferons (INFs) in the body of the patient. Antitumour efficacy of TNF has been confirmed in animal models, in which it has been observed to inhibit growth or result in complete regression of the tumour8,17.

Furthermore, it has also been confirmed that the antitumour effect of Coley’s toxin could be mediated by the production of IL-12, known to extend the function of pre-existing tumour-specific T cells for subsequent induction of signals required for tumour regression. IL-12 receptors are preferentially expressed on activated T-cells, and this explains why the therapy with IL-12 is effective against pre-existing tumours5.

The last recorded successful application of the toxin was in China in 1980 as a primary therapy for the treatment of terminal liver cancer. The patient received 68 injections of Coley’s toxin during the 34 weeks of therapy. After this procedure, the symptoms disappeared completely2.

Bacillus Calmette-Guérin

The observation that the presence of bacterial infection results in the stimulation of the immune system has led to the clinical use of BCG (Mycobacterium bovis) in the treatment of superficial urinary bladder cancer5. It is considered to be the most successful form of immunotherapy, and this method has become the standard for treatment of this type of tumour. The vaccine strain ofM. bovis is injected directly into the bladder3,18.

Many studies have shown a clear correlation between the usage of BCG after surgical removal of the tumour and the subsequent decrease or delay in the risk for cancer recurrence. Almost 60% of the patients showed no signs of tumour recurrence14,19,20.

The antitumour effect of the vaccine is based on the induction of a local immune response and the production of cytokines such as IL-2, TNF-α and INF-γ. After intravesical administration of the vaccine, IL-1, IL-6, IL-8, IL-10, IL-12, IL-18 and macrophage colony stimulating factor were detected in urine over the course of the disease. Similar to Coley’s toxin, the application of BCG requires long-term administration. The possible influence of BCG on the reduction of colorectal carcinoma has also been studied5,8,11,12,21.

It has been previously mentioned that the anti-tumour effect of the BCG vaccine could be due to its effect of decreasing the proliferation of tumour cells, along with production of the cytokines mentioned above20. Unfortunately, this method of treatment also had significant toxicity and was inefficient in 30–50% of cases5.

Clostridium spp. and other anaerobic bacteria

Hypoxia is a pathophysiological feature in the majority of solid tumours. Hypoxic areas in poorly vascularized cancers that make the effective distribution of an active drug difficult are the main barriers to successful cancer therapy. The blood vessels in tumours are structurally and functionally abnormal, resulting in heterogeneous blood supply13,22.

The hypoxic microenvironment in solid cancers is ideal for survival and multiplication of anaerobic bacteria. Healthy tissue, where blood supply is sufficient, is therefore not attacked by the bacteria. It was assumed that their application into the tumour should yield expected therapeutic effect. This assumption was confirmed in the 1960s22,23.

Over the next 50 years, several strains of facultative and obligate anaerobic bacteria were tested as potential therapeutic agents for the induction of spontaneous regression of tumours. These bacteria were localized to cancer tissue, and lysis of tumours was observed in experimental animal models. These promising data resulted in trial studies initiated in the 1960s that use bacteria of the genusClostridium. However, the results were not as good as expected and the studies were terminated5,13,24.

Besides the above-mentioned genusClostridium, bifidobacteria and lactobacilli were the other microorganisms tested as potential therapeutic agents inducing tumour regression. These bacterial strains were shown to be highly selective and localized primarily within the tumour cells5,21.

Clostridium spp.

Clostridium spp. was shown to cause tumour regression in a rodent model. However, in subsequent clinical studies in human populations, significant therapeutic effect was not demonstrated. The toxic effects after administration of these bacteria exceeded the beneficial effects22.

As mentioned above, clostridia have the unique property of proliferating in the necrotic areas of the tumour under hypoxic conditions. Unfortunately, in many animal models, acute toxicity or even mortality of the tested subject was observed.

In 1935, Connell used sterile filtrates fromC.histolyticum to treat advanced forms of cancers. The observed tumour regression was attributed to the production of proteolytic enzymes. Mengesha25 mentioned that the setup with deliberate colonization of tumour-bearing mice with clostridial spores was first used in 1947.

A typical example of this genus isC. novyi, which showed significant antitumour effect during experiments in laboratory animals. Spores ofC. novyi were systematically injected into the animal, in which they grew perfectly in the hypoxic tumour environment. Thirty per cent of the mice treated with these spores were cured of their tumours, although the tumour margin remained visible after the germination of the spores. However, the majority of these cases resulted in the death of the animal21,22,24. For this reason, the attenuated strainC. novyi-NT was developed by genetic modification, with deletion of the gene encoding the lethal toxin. Satisfactory results were obtained; however, toxicity was still present, thus making it unsuitable for tumour therapy13,24.

To avoid the toxicity, nonpathogenic strains ofC. oncolyticum were also used13. Application of theClostridium spp. strain M55 resulted in colonization of necrotic areas of the tumour, but cancer regression was not observed26.

C. perfringens was shown to be capable of colonizing in advanced stages of selective pancreatic cancers and inducing progressive necrosis in the tumours. The possibilities of conventional methods of treatment (radiotherapy and chemotherapy) are limited in this type of cancer and the response to conventional therapy is poor22.

Bifidobacterium spp.

The genusBifidobacterium, another promising representative of anaerobic bacteria, is also considered a possible candidate for cancer therapy. Attention is focused mainly on the following three representatives:B. longum,B. infantis andB. adolescentis10.

B. longum is a nonmotile bacterium that remains, survives and grows under the anaerobic conditions of a tumour. After intravenous administration ofB. longum in mice with tumours, no additional visible symptoms were observed. It has been repeatedly proven that the bacteria disappear from normal tissues or organs such as the liver, kidneys, lungs, blood and bone marrow 48–96 h after administration and grow only in the tumour. Within 1 h, 10² CFU/g of bacteria, and by day 7, 10⁶ CFU/g of bacteria were present in the tumour. Unfortunately, there was no antitumour effect10,21. In another studyB. adolescentis was tested, and this bacteria was shown to prevent the occurrence and development of colorectal cancer and induce apoptosis in an animal model10.

Lactobacillus spp.

Lactobacilli are generally considered as safe microorganisms, and they have been studied for a wide range of possible applications. Experimental studies have shown that oral administration of lactobacilli may contribute to the reduction of recurrence of urinary bladder cancer. It has been proven that lactobacilli on administration inhibit chemically induced carcinogenesis and reduce tumour growth in animal models27.

Salmonella spp.

Bacteria of the genusSalmonella are facultative anaerobic bacteria and are able to grow in both aerobic and anaerobic environments.S. enterica, serovar Typhimurium has been reported to cause spontaneous regression of cancer after intravenous administration of live attenuated vaccines in mice with growing tumours23. More than 50 years ago, it was demonstrated that this bacterium can colonize human tumours, and a ratio of microorganisms in the tumour to those in healthy tissue of 10³–10⁴ : 1 was mentioned5,28.

TheSalmonella spp. strainVNP20009 was successfully developed for use in anticancer therapy. Deletion ofMsbB andpurL genes resulted in complete attenuation and elimination of potential adverse effects after its application. Some strains of this genus induce clinical conditions associated with septic shock. This vector showed a long lasting efficacy against a broad spectrum of carcinomas, and it targeted the metastatic lesions as well5,24. TheSalmonella strainVPN20009 was used in the USA in phase I of testing for the treatment of metastatic melanoma and renal cancer. The minimum tolerated dose in relation to the toxicity was determined to be 3×10⁸/body surface (m²), and the presence ofSalmonella was detected by biopsy of tissue. Regression of cancer was not observed in any patient, and only in three patients was the presence of bacteria demonstrated by biopsy. In four patients, symptoms associated with the presence of bacterial infection were described. However, no bacteria were found in the biopsy samples. Their identification was confirmed by excision of whole tumour tissues21. Overall, it could be concluded that the results of application of this bacterial strain were not satisfactory. Only high doses and repeated administration of these bacteria led to colonization of the tumour, but the therapeutic effect was unremarkable29.

S. typhimurium strain A1 proliferates in tumour xenografts but not in normal tissue. It is auxotrophic (leu/arg-dependent) and only grows locally. ReisolatedS. typhimurium A1 strain (from A1-targeted tumour), named A1-R, inhibited, and in some cases even eradicated, primary and metastatic tumours.In vivo, these bacteria caused human prostatic cancer cell inhibition and subsequent regression of subcutaneous xenografts30,31.

Strain A1-R administered intravenously induced human breast cancer regression and cured cancer in nude mouse models32,33. Furthermore, breast-cancer brain metastases were significantly inhibited by this bacterial strain in mouse models34. Uchogonovaet al.35 and Liuet al.36 reported that the A1-R strain was highly effective against lung carcinoma, especially against metastases in nude mice.

S. typhimurium A1-R has a promising effect on disseminated ovarian cancer, especially after intraperitoneal administration in nude mouse models. Clinical application ofS. typhimurium A1-R was suggested for ovarian cancer, a highly treatment-resistant disease37,38. Potential therapeutic usage of these bacteria in cervical carcinoma has also been mentioned39.

A significant effect of the A1-R strain against pancreatic cancer has been described in different mouse models [nude, C57BL/6 and C57BL/6 CD8−/− (B6.129S2-CD8atm1Mak/J mice)], and the clinical implications have been described40–45. For sarcoma and glioma treatment, a potential therapeutic effect of the A1-R strain has been suggested as well46–51.

The antitumour activity ofSalmonella spp. has been previously described. The production of a wide spectrum of enzymes by bacterial species could be one of the mechanisms that lead to the apoptosis of tumour cells. It has been reported that induction of apoptosis in cancer correlated with the accumulation ofSalmonella spp. in tumours. Autophagy could also be another mechanism of tumour cell apoptosis. Inhibition of apoptosis of the infected cancer leads to an increase in autophagy28.

Other tested microorganisms

The following microbial agents have been tested as potential anticancer agents or for the production of vaccines:S. cholerae suis,Vibrio cholerae,Listeria monocytogenes andEscherichia coli24.

Spontaneous regression has also been associated with other bacterial infections such as diphtheria, gonorrhoea, syphilis and tuberculosis; viral diseases like hepatitis, influenza, rubella and smallpox; and other purulent or nonpurulent diseases2.

Bacteria and viruses are not the only agents that can induce tumour regression in an infected host. Protozoans such asToxoplasma gondii andBesnoitia jellisoni can also activate macrophages and induce tumour regression23.

Anticancer methods using microorganisms

Commonly used anticancer methods using microorganisms comprise bactofection, alternative gene therapy, combined bacteriolytic therapy and bacteria-directed enzyme prodrug therapy. For more details, see Table1. Special categories of cancer treatment using microbial peptides have been described in Table2.

Role of the immune system in spontaneous regression of cancer

As mentioned above, spontaneous regression of tumours is associated with bacterial, viral, fungal or protozoan infections.

The duality of the immune system

An important factor that applies to the regression of cancer is the duality of the immune system. In the defensive mode, there is regression of the tumour and cells of the immune system are produced. Conversely, in the reparative mode, progression is facilitated and invasiveness is increased by the production of immunosuppressive cytokines, growth factors, angiogenic factors and matrix metalloproteinases. The defensive mode is active during an ongoing infectious disease8,12. A considerable number of studies confirm that tumour infiltrating leucocytes are not successful in inhibiting the growth of tumours; however, they are actively involved in the progression of cancer through their reparative functions57.

The immune system versus bacteria versus spontaneous regression of cancer

Infection of tumours leads to infiltration by lymphocytes and antigen-presenting cells such as macrophages and dendritic cells (DCs). Binding of pathogen-associated molecular patterns to toll-like receptors on antigen-presenting cells induces activation and antigen presentation. Induction leads to the production of important costimulatory molecules such as B7 and IL-12, resulting in the activation of the immune system12. DCs can be stimulated primarily by lipopolysaccharides of Gram-negative bacteria or by other bacterial or viral products. The present bacterial infection has a three-fold effect on their stimulation. Large numbers of bacteria possessing lipopolysaccharides induce the production of cytokines; the production of thymocytes and cytotoxic T lymphocytes (CTL) increasesin vitro during the rise of temperature. Cancer cells can be more sensitive to heat than normal cells; infections that cause haemorrhagic necrosis could trigger collapse of the vasculature of the tumour because of fever7,58. Febrile illness could play a role in remission of cancer because fever can lead to the release of a cascade of proinflammatory factors capable of stimulating DCs and resulting in T-cell activation7.

It has been suggested that regression is related to cellular rather than humoral immunity. In Coley’s experiments, it has been described that tumour regression occurred several hours after injection of the toxin, and discontinuation of therapy for even a day resulted in reappearance of the tumour from its residual tissue. Antitumour immunity was mediated by innate and nonspecific immune responses rather than by the slower adaptive immunity. For this reason, Coley had recommended daily injection of the toxin8,23.

T lymphocytes are responsible for cell-mediated immunity, and B cells for humoral immunity. B-cells play a role in the destruction of tumours by lysis mediated by complement activation and facilitate antibody-dependent cell-mediated cytotoxicity. CTL and natural killer (NK) cells are important in inducing tumour lysis. CTL cells recognize major histocompatibility complex antigens on the cell membrane and NK cells seek out and kill the tumour cells, thus playing an important role in the prevention of metastases6.

Oikonomopoulou and colleagues reported that some pathogens express antigens that cross-react with tumour-associated antigens. Thomsen-Friedenreich (T) and Tn parasitic antigens were detected in more than 80% of cancer patients, and appear to be potential markers for clinical use. In addition, in sera obtained from patients with parasitic infections (Echinococcus), cross-reactivity is often observed with sera gained from patients with carcinoma. Interestingly, these sera are frequently present in patients with less-extensive tumours. Antibodies against these shared antigens can potentially target the tumour cells to be destroyed or increase the presentation of antigens to T cells and thus induce an antitumour response59.

Another interesting finding was that, in mice bearing melanoma infected withT. gondii tumour, regression was observed without current activation of CTLs and NK cells, production of NO by macrophages and IL-12 or TNF release. The authors found that the tissues infected byT. gondii produced some factors that prevent the formation of blood vessels in tumour tissue. As a result, hypoxia occurs and therefore causes necrosis and subsequent cell death. The authors consider that inhibition of angiogenesis during infection could be caused by synthesis of soluble antiangiogenic factors by infected tissues, which could serve as a potential therapeutic agent like endostatin (endogenous angiogenesis inhibitor)23,59.

Factors related to microorganisms and macroorganism versus spontaneous regression of tumour

Factors related to microorganisms comprise microbial products and pathogen-associated molecular patterns (extracellular and intracellular microorganisms) and subsequent activation of an appropriate immune response. For more information, see Fig.1. Figure2 informs the readers about the factors related to macroorganism with regard to subsequent possible spontaneous regression of tumours (immune system, receptors, mediators, cells, etc.)

Other mechanisms

Mager mentions an interesting study on the mechanism that could potentially contribute to the spontaneous regression of cancer. The tumour regression observed after the administration of Coley’s toxin was caused by activation of plasminogen. In that case, the bacterial enzyme streptokinase (product of bacteriaStr. pyogenes) acts on the plasminogen of the host, resulting in the release of plasmin. Plasmin triggers a cascade of proteases that degrade the plasma and extracellular matrix proteins. These mechanisms are fatal for tumour cells as they disrupt the extracellular matrix of the tumour, suspend its subsequent growth and reduce the risk for metastases7.

Conclusion

Spontaneous regression of cancer associated with the presence of microbial agents is a very important treatment option for cancer. These new therapeutic approaches, aimed at application of killed or genetically modified microorganisms as vaccines, could significantly reduce the side effects of other more commonly used methods of cancer therapy like chemotherapy and radiotherapy. The phenomenon of spontaneous regression of cancer is also one of the key areas of research in our laboratory, because of the spontaneous regression of hereditary melanoma observed in the Melanoma-bearing Libechov Minipig (MeLiM). Bacterial strains ofStaphylococcus spp. [Staphylococcus (St.)hyicus,St. epidermidis,St. lentis,St. hyicus, etc.],Streptococcus spp. (Str. uberis,Str. equi,Str. Dysgalactiae, etc.), and Enterobacteriaceae (E. coli,Klebsiella pneumoniae), as well as yeast (Candida lipolytica) have been cultivated from cutaneous and melanoma smears from the minipigs in our laboratory. It could be hypothesized that the production of specific enzymes by these microorganisms could induce immune mechanisms leading to spontaneous regression of malignant melanoma in the MeLiM model. Until now, we have failed to identify the exact mechanisms of melanoma regression. The presence of specific strains of microorganisms in the tumours of our minipigs could provide us with a vital clue that connects spontaneous regression with microorganisms.

Conflicts of interest

There are no conflicts of interest.

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