Bacteria-Mediated Synergistic Cancer Therapy: Small Microbiome Has a Big Hope

Abstract

The use of bacteria to specifically migrate to cancerous tissue and elicit an antitumor immune response provides a promising platform against cancer with significantly high potency. With dozens of clinical trials underway, some researchers hold the following views: “humans are nearing the first commercial live bacteria therapeutic.” However, the facultative anaerobe Salmonella typhimurium VNP20009, which is particularly safe and shows anticancer effects in preclinical studies, had failed in a phase I clinical trial due to low tumor regression and undesired dose-dependent side effects. This is almost certain to disappoint people’s inflated expectations, but it is noted that recent state-of-the-art research has turned attention to bacteria-mediated synergistic cancer therapy (BMSCT). In this review, the foundation of bacteria-mediated bio-therapy is outlined. Then, we summarize the potential benefits and challenges of bacterial bio-therapy in combination with different traditional anticancer therapeutic modalities (chemotherapy, photothermal therapy, reactive oxygen and nitrogen species therapy, immunotherapy, or prodrug-activating therapy) in the past 5 years. Next, we discuss multiple administration routes of BMSCT, highlighting potentiated antitumor responses and avoidance of potential side effects. Finally, we envision the opportunities and challenges for BMSCT development, with the purpose of inspiring medicinal scientists to widely utilize the microbiome approach in patient populations.

Yeast-derived nanoparticles remodel the immunosuppressive microenvironment in tumor and tumor-draining lymph nodes to suppress tumor growth

“…Firstly, due to their potential to cause infections in patients, live microbes may cause the immune system to attack healthy cells, and their use may be in company with the risk of deadly infection. In addition, the facultative anaerobe Salmonella typhimurium VNP20009 failed in a phase I clinical trial because the monotherapy was found not enough to eliminate tumor effectively 20 . Microbe-based cancer immunotherapy is still in its early stage 21 .…”

Tumor Temporal Proteome Profiling Reveals the Immunological Triple Offensive Induced by Synthetic Anti-Cancer Salmonella

“…Although bacteria-mediated tumor therapy could be recognized as the oldest type of cancer immunotherapy, its proper clinical application still needs to fulfill very strict requirements of safety and efficacy in both mechanistic and large scale (pre-)clinical studies ( 8 , 54 ). Early bacteria-based antitumor drug like Coley’s toxin was made of natural pathogen, which showed clear efficacy against multiple types of tumor but suffered from toxicity ( 4 , 8 ).…”

“…Nearly Two decades ago, the attenuated salmonella VNP20009 was approved to enter a phase I clinical trial, in which its safety was clearly proved but efficacy was insignificant ( 55 ). These days, the emerging synthetic biology technology provided more possibilities for engineering both safe and efficient antitumor bacteria, and combining the synthetic bacteria with other tumor killing agents ( 13 , 15 , 54 , 56 , 57 ). These advances together shed a light on the future of understanding and applying the bacteria-mediated tumor therapy clinically.…”

Bacteria-Based Microdevices for the Oral Delivery of Macromolecules

“…Subsequently, more bacterial species, including Bifidobacterium spp., Clostridium spp., S. typhimurium, and E. coli, have been found to accumulate in tumor sites [25]. In light of their inherent capacities of breaking related biological barriers and colonizing tumor tissue, these bacterial species have been intensively attracted for cancer therapy [107,108]. Moreover, equipped with technologies progressed rapidly in gene editing and bio-interface science, bacteria have been engineered to act as vehicles for the delivery of therapeutic agents including both small molecules and biomacromolecules (proteins and DNAs) (Table 2) [20,54,64,100,109].…”