Integration of Salmonella into Combination Cancer Therapy

Abstract

Current modalities of cancer treatment have limitations related to poor target selectivity, resistance to treatment, and low response rates in patients. Accumulating evidence over the past few decades has demonstrated the capacity of several strains of bacteria to exert anti-tumor activities. Salmonella is the most extensively studied entity in bacterial-mediated cancer therapy, and has a good potential to induce direct tumor cell killing and manipulate the immune components of the tumor microenvironment in favor of tumor inhibition. In addition, Salmonella possesses some advantages over other approaches of cancer therapy, including high tumor specificity, deep tissue penetration, and engineering plasticity. These aspects underscore the potential of utilizing Salmonella in combination with other cancer therapeutics to improve treatment effectiveness. Herein, we describe the advantages that make Salmonella a good candidate for combination cancer therapy and summarize the findings of representative studies that aimed to investigate the therapeutic outcome of combination therapies involving Salmonella. We also highlight issues associated with their application in clinical use.

The Evolution and Future of Targeted Cancer Therapy: From Nanoparticles, Oncolytic Viruses, and Oncolytic Bacteria to the Treatment of Solid Tumors

“…Once there, they are able to penetrate the desmoplasia from blood vasculature into the hypoxic tumor core, a difficult if not impossible task for most other chemotherapeutics, where they not only lyse the tumor, but act as a potent, life-long reactivation of the immune system against genetically similar tumors [28,191,[193][194][195]. The potential of this particular species is furthered as the fully lytically capable, vegetative form cannot survive in any measurable level of oxygenation such as found in the blood stream or urine, and the spores, which are able to mitigate the toxic effects of oxygen, cannot initiate germination in any physiological level of oxygen, thus alleviating the risk of off-target events [162,187,189,194,196]. Improving the tumor localization capacity of C. novyi through CRISPR-mediated, stable genomic incorporation of an RGD peptide on the spore coat has recently been demonstrated feasible, indicating a promising new direction for customization to elicit better oncolytic capacity [157].…”

“…Improving the tumor localization capacity of C. novyi through CRISPR-mediated, stable genomic incorporation of an RGD peptide on the spore coat has recently been demonstrated feasible, indicating a promising new direction for customization to elicit better oncolytic capacity [157]. In contrast, Salmonella and Listeria species not only survive but proliferate in most intracellularly oxygenated environments, increasing the potential risk for off-target toxicity [196]. Salmonella use their flagellated membrane to migrate towards high nutrient concentrations produced primarily within the TME [182][183][184][185].…”

Highlights of Immunomodulation in Salmonella-Based Cancer Therapy

“…These combinatorial therapies have shown eradication of tumors which may be an outcome of activating radiation-induced tumor cell death. The role of tumor-specific immunity in this context may be investigated further, as a report suggests that the ionizing radiation contributes to immunogenic tumor cell death [ 120 ]. Therapeutic combinations with other existing treatment approaches or interventions have also been reported to enhance the effect of Salmonella -based treatment in modulating tumor-specific immune responses [ 120 ].…”

“…The role of tumor-specific immunity in this context may be investigated further, as a report suggests that the ionizing radiation contributes to immunogenic tumor cell death [ 120 ]. Therapeutic combinations with other existing treatment approaches or interventions have also been reported to enhance the effect of Salmonella -based treatment in modulating tumor-specific immune responses [ 120 ]. For instance, we previously reported that Salmonella treatment did enhance tumor chemosensitivity to cisplatin via Cx43 upregulation [ 121 ].…”

Comparison of Anticancer Activities and Biosafety Between Salmonella enterica Serovar Typhimurium ΔppGpp and VNP20009 in a Murine Cancer Model

“…Among them, S. Typhimurium has been widely used in cancer treatment due to its specific tumor targeting ability and colonization to overcome the shortcomings of traditional cancer treatments, such as insufficient tumor selectivity and poor tissue penetration. Engineered S. Typhimurium has good biosafety, tumor targeting, and capacity to carry or express anticancer payloads, thereby providing suitable conditions for the combination of BMCT with other therapeutics ( Guo et al, 2020 ; Al-Saafeen et al, 2021 ).…”