Bacteria in Cancer Therapy: Renaissance of an Old Concept

Abstract

The rising incidence of cancer cases worldwide generates an urgent need of novel treatment options. Applying bacteria may represent a valuable therapeutic variant that is intensively investigated nowadays. Interestingly, the idea to apply bacteria wittingly or unwittingly dates back to ancient times and was revived in the 19th century mainly by the pioneer William Coley. This review summarizes and compares the results of the past 150 years in bacteria mediated tumor therapy from preclinical to clinical studies. Lessons we have learned from the past provide a solid foundation on which to base future efforts. In this regard, several perspectives are discussed by which bacteria in addition to their intrinsic antitumor effect can be used as vector systems that shuttle therapeutic compounds into the tumor. Strategic solutions like these provide a sound and more apt exploitation of bacteria that may overcome limitations of conventional therapies.

Figure 1

Biological events of the intrinsic tumor therapeutic effect of Salmonella. Steps  (1)–(4) depict major biological events associated with an antitumor effect induced by Salmonella infection. (1) Tumor invasion. (2) Colonization. (3) Infection control. (4) Antitumor response and tumor regression. (1) Presence of bacteria in the blood stream (bacteremia) induces a cytokine storm, which is dominated by vasoactive cytokines that facilitate passive deposition of bacteria in the tumor during the induced hemorrhage. (2) Invading bacteria accumulate, localize to a preferable growth environment (low p0₂, immune privileged site), and proliferate to saturation. (3) Colonization brings about change to the tumor microenvironment, including attraction and polarization of innate effector cells and cytokines in favor of antibacterial control and tumor immune surveillance. (4) Tumor regression occurs in response to multimodal therapeutic effects, including an adjuvant effect on preestablished tumor immune surveillance, polarization of innate effectors' phenotype, direct cytotoxicity, and passive effects.

Figure 2

Hypothetical relationship between intrinsic therapeutic benefit and safety using Salmonella for bacteria mediated tumor therapy. Empirical observations support an inverse relationship between intrinsic therapeutic benefit and safety of treatment associated with Salmonella-based tumor therapy. Strain variants A–C in order of increased attenuation. Depicted are three scenarios, each intrinsically inadequate for achieving therapeutic success. Reinstalling/complementing an intrinsic therapeutic effect may be accomplished via recombinant strengthening without affecting the aforementioned intrinsic relationship.

Figure 3

Various phenotypic outcomes in mice following treatment with Salmonella. The inverse relationship between intrinsic therapeutic benefit and safety of bacteria mediated tumor therapy (BMTT) using Salmonella can be demonstrated through manifestation and progression of cancer and infection in mice. An inadequately attenuated, thus virulent, strain may successfully retard/regress tumor development albeit concurrently resulting in morbidity and mortality of the patient (strain A). Conversely, overattenuation may ensure patient safety at the cost of therapeutic efficacy (strain C). Intermediate levels of attenuation may yield corresponding levels of cancer progression and manifestation of infection (strain B). Thus, developing a properly balanced strain remains a challenge for successful therapy using Salmonella.