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The escalating incidence of cancer cases worldwide promotes a crucial need of new treatment options. As a matter of fact, applying bacteria for this purpose would definitely introduce a valuable therapeutic variants which are being explored at the moment. Stimulatingly, the notion of applying bacteria wittingly or unwittingly appeared a very long time ago, and reappeared again in the 19th century by the famous pioneer William Coley. This review will mainly summarize and give a concrete comparison of the results found during the past 150 years in bacteria mediated tumor therapy from preclinical to clinical approaches.In fact, for the majority of cancer patients’ diagnosis is a synonym to suffering, intoxicating therapies with a very low outcome not to say a mortal one. However, during the past 50 years, this insight has slightly improved; knowing that cancer is still nowadays as the second most recurrent origin for death. Undoubtedly, several molecular modifications are needed for the genome of a cell in order to modify a regular cell into a cancerous one. Therefore, the chances that such processes will occur in an individual cell is definitely increasing with the factor of age. According to recent statistics, it was discovered that every second individual will have cancer throughout his/her life and every fourth will ultimately die from the disease. Surely, from those given data we can have a brief overview of cancer and its tremendous impact on modern society, in addition to the crucial need of numerous therapies to be developed for this purpose.In fact, common therapies such as radiotherapy, surgery, chemotherapy are still considered as the backbone of cancer therapy until these days.  Nevertheless, not all cancerous tissue can be selected by the use of chemical or physical methods due to the fact that it would be very challenging to distinguish properly between malignant and healthy tissues. For the purpose to overcome those downsides, extensive research was done in order to expand the knowledge on carcinogenesis.  The latter showed that cancer has indeed a multifactorial type of disease.The immune surveillance is very often accepted as the hosts own defense system against the propagation of cancer in cells. Still, once these tumors are formed, they may become very resistant to immune destruction due to two reasons which are Darwinian selection of mechanisms of immune editing.  Consequently, under such conditions a physiological consequences of this unevenness may lead to a tumor microenvironment of repair instead of destruction.  In fact, active cancer immunotherapy targets to reserve this imbalance with the help of compensatory immune activity. William coleyThe first report initiating a crucial connection between both infections and treatment for swellings; most likely cancerous tissues was mainly done by the physician Imhotep 2600 BC. Afterwards, tumor retardation was mainly perceived by in cancer patients dealing with gas gangrene, and which we know now that it is caused by Clostridia sp. The first clinical trial was realized by W. Busch and some of his colleagues in Berlin in 1863, what they did was infecting a patient intentionally by transferring her into a contaminated bed of an earlier patient who died from Erysipelas(infection triggered by Streptococcus pyogenes). By doing so, the patient got infected indeed; however, the tumor started to decrease little by little but the patient ended up dying from the infection.  Undoubtedly, the failure to control bacterial infections back then was a limiting factor in terms of clinical applications.Inspired by those previous facts and trials, William Coley, a very known American Physician, became indeed the first pioneer in the field of cancer immunotherapy.  At the beginning he mainly started by live bacteria, being even able to kill his actual patients. In fact, he was the first to realize that a precise balance between infection control and therapeutic benefit was necessary for the viability of this type of treatment. For this purpose, he used a mixture of heat-inactivated Streptococcus pyogenes and Serratia marcescens on several patients affected with inoperable sarcomas. Indeed, the following discovery has a very effective use.  In addition to this, along his career he used his ‘toxin’ to an important number of patients. Whenever he has a chance he injected it directly into the primary tumor mass by multiplying the dose along the process of therapy. One of the common side effects that he was observing very frequently was fever. However according to his records, episodes of fever, and an excessive treatment were having a high correlation with the success of his therapy. In fact, tumor regression was noticed in an endless number of patients, and for some of them even complete clearance was observed that led to disease free state at the end. Current Concepts of Bacteria Mediated Cancer Therapy Even though Coley’s work had a great success back then; however, his work was not recognized right away until the approach had been approved in 1936 by the AMA after his death. One of these reasons would be that he couldn’t explain properly the therapeutic mechanism in addition to the side effects that may occur after the therapy. Afterwards, during 1960 and 1970s, same clinical trials were done with identical formulations as Coley’s toxin such as Vaccineurin; however, the results found were very variable from one experience to another. Moreover, a controlled study accomplished on 1962 revealed that a therapeutic response occurred only on 20 individuals out of 93 cancer patients showing that there were several differences among individuals in terms of susceptibility in the given therapy.  By the use of animal models, in addition to Gram-positive, and Gram-negative bacteria of various genera of Clostridiasp., Salmonella sp., Bifidobacteria sp., and Listeria sp have been tested for their potential in cancer therapy.During the last half of the 20th century, obligate anaerobic bacteria such as Clostridia spores were used for the purpose of cancer therapies. Indeed, these spores develop only while the oxygen is absent. Consequently, these bacteria are specific for necrotic areas, which is a common and unique feature for solid tumors. Even though the growth of Closridia was mainly associated with hypoxic regions, toxicity conferred by exotoxins caused an important mortality rates using this bacteria. As a matter of fact, in order to have a better safety for Clostridia, ?-toxin (virulence factors) were deleted from potential therapeutic strains.  Additionally, C. novyi-NT (nontoxic) was tested in both preclinical and clinical trials for both dogs and humans. Therefore, the found results were favorable in addition to the advanced leiomyosarcoma of a patient was successfully affected while doing an intratumoral injection of Clostridia spores. Moreover, recent studies showed as well that orthotopic glioblastomas were positively targeted with C.novyi spores while having an intravenous infection in a rat model. Consequently, these results showed us that spores are capable of passing blood brain barrier under some conditions. Even though the mechanism is not well understood in terms of antitumor effect by Clostridia, still yet these bacteria are able to target neoplastic tissue without having any bad effect on the host.In order to overcome the restriction of confinement to hypoxic regions and to have a concrete idea about the growth of tumors from viable oxygenated tissue; some facultative anaerobic bacteria such as Salmonella Typhimurium were highlighted for the purpose to come up with new solutions for cancer therapies. In fact, Salmonella is capable of growing under aerobic conditions and is not only narrowed for colonizing tumors but can have several other functions like propagating into healthy organs such as the spleen and liver. With that being said, Salmonella should definitely be adapted and controlled in order to ensure safe application; meaning that a certain level of control is needed for this therapy to be successful. As Coley observed on his previous constatations that for S.pyogenes, wild-type bacteria are efficient for destroying cancerous tissue; however, this may cause some issues for the patients. In an attempt to find a solution to this concern, he decided to heat inactivation even though the therapy wont be effective as before. Concerning his later attempts, he also tried genetic alteration for the purpose to  use safer treatments. In fact, suitable strains have been created during the past decades. Thy are obtained by several methods such as by in vitro or in vivo passaging or by the use of molecular techniques for the purpose to get the targeted gene deletion. Indeed, this first method depends mainly on the selective pressure when the given bacteria is getting adjusted to a certain environment within the host. By transiting bacteria from tumor to tumor either in mice or cell culture, it is possible for them to evolve a tumor adapted phenotype simultaneously showing high tumor specificity.  The Salmonella strains VNP20009 (in vitro) and A1-R (in vitro and in vivo) appeared from this type of strategy. Auxotrophy for purines or Arg and Leu,correspondingly, rendered these Salmonella variants metabolically deficient and increased tumor specificity. Especially, the starin A-1-R was observed to be very effective in several cancer models. in fact, the random insertion of some deletions or single point mutations through selective pressure represents an unmanageable way to properly modify or adjust bacterial strains. It was stated that VNP20009 was by coincidence bearing a deletion of 120 genes which may affect its in vivo performance. More than that, it contains a SNP in the chemotaxis gene cheZ. Consequently, the whole flagella synthesis is impaired. The strain was therefore devoid of a potent immune-stimulating factor.. Due to the uncertainties affiliated with such an unspecified method of attenuation illustrated by the previous examples, targeted gene deletion may be a better choice for tailoring bacteria for cancer therapy.

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