Therapy of solid tumors using probiotic Symbioflor-2 - restraints and potential

Abstract

To date, virulent bacteria remain the basis of most bacteria mediated cancer therapies. For clinical application attenuation is required. However, this might result in a drastically lowered therapeutic capacity. Herein we argue that the E. coli probiotic Symbioflor-2, with a history of safe application may constitute a viable tumor therapeutic candidate. We demonstrate that Symbioflor-2 displays a highly specific tumor targeting ability as determined in murine CT26 and RenCa tumor models. The excellent specificity was ascribed to reduced levels of adverse colonization. A high safety standard was demonstrated in WT and Rag1−/− mice. Thus, Symbioflor-2 may represent an ideal tumor targeting delivery system for therapeutic molecules. Moreover, Symbioflor-2 was capable of inducing CT26 tumor clearance as result of an adjuvant effect on tumor specific CD8+ T cells analogous to the Salmonella variant SL7207. However, lower therapeutic efficacy against RenCa tumors suggested a generally reduced therapeutic potency for probiotics. Interestingly, concurrent depletion of Gr-1+ or Ly6G+ cells installed therapeutic efficacy equal to SL7207, thus highlighting the role of innate effector cells in restraining the anti-tumor effects of Symbioflor-2. Collectively, our findings argue for a strategy of safe strain application and a more sustainable use of bacteria as a delivery system for therapeutic molecules.

Use of Bacteria in Cancer Therapy (Review)

“…Особый интерес представляют результаты оценки противоопухолевого потенциала непатогенных бактерий -представителей собственной нормофлоры человека, а именно: Bifidobacterium spp., Lactobacillus spp. (анаэробы), Escherichia coli (факультативный анаэроб) [20][21][22][23]. Показано, в частности, что бактерии Bifidobacterium longum способны к транслокации из кишечника во внутреннюю среду организма с фиксацией в макрофагах печени, обеспечивая при этом высокий уровень колонизации опухоли молочной железы у крыс [20].…”

Advances in bacterial cancer therapies using synthetic biology

“…While it is also a Gram-negative facultative anaerobe, unlike S. typhimurium , it has non-pathogenic variants naturally found in the human gut (commensal strains, some of which are probiotics that have a positive effect on health when given) [68]. The ability to make use of these strains without further attenuation and their status as clinically approved probiotics makes them attractive candidates for use in therapies [69]. The most common probiotic strain in use is E. coli Nissle 1917, but alternative strains have been explored [41,69].…”

“…The ability to make use of these strains without further attenuation and their status as clinically approved probiotics makes them attractive candidates for use in therapies [69]. The most common probiotic strain in use is E. coli Nissle 1917, but alternative strains have been explored [41,69]. While E. coli has been used more than S. typhimurium in the overall field of synthetic biology, Prindle et al demonstrated that significant genetic circuits built in E. coli could be transferred to the more clinically used S. typhimurium , noting that these two species have similar ease of engineering as they have fully sequenced genomes, knockout collections, and easily used tools for genetic manipulation [70].…”

“…While in some cases the bacterium itself is the therapeutic, bacteria are most often used to locally and specifically deliver a therapeutic molecule of interest, as controlled local delivery can mitigate unwanted off-target effects compared to delivering a therapeutic systemically [15,16,69]. Many reviews have detailed therapeutics used; they broadly fall under two types: proteins and nucleic acids [64,84,85].…”

Tumour‐targeting bacteria‐based cancer therapies for increased specificity and improved outcome

“…It was found to prevent relapses of superficial bladder cancer to a high degree and has been deployed in the clinics already since the late 1980s. Further promising candidates for BMTT include Gram-positive bacteria like Listeria monocytogenes or Clostridium novyi-NT and Gram-negative bacteria like Salmonella Typhimurium and Escherichia coli (Paterson et al, 2010;Kubiak and Minton, 2015;Felgner et al, 2016a;Kocijancic et al, 2016). Although the concepts to apply the various bacteria for cancer therapy differ significantly, they have all been able to demonstrate antitumour properties in preclinical models and some even in clinical trials.…”