Bactofection, Bacterial-Mediated Vaccination, and Cancer Therapy: Current Applications and Future Perspectives

Abstract

From the first report in 1891 by Dr. Coley of the effective treatment of tumors in 1000 patients with Streptococcus and the first successful use of bacterial vectors for transferring therapeutic genes in 1980 by Dr. Schnaffer, bactofection has been shown to be a promising strategy in the fields of vaccination, gene therapy, and cancer therapy. This review describes the general theory of bactofection and its advantages, disadvantages, challenges, and expectations, compiling the most notable advances in 14 vaccination studies, 27 cancer therapy studies, and 13 clinical trials. It also describes the current scope of bactofection and promising results. The extensive knowledge of Salmonella biology, as well as the multiple adequacies of the Ty21a vaccination platform, has allowed notable developments worldwide that have mainly been reflected in therapeutic efforts against cancer. In this regard, we strongly recommend the creation of a recombinant Ty21a model that constitutively expresses the GtgE protease from S. typhimurium, allowing this vector to be used in animal trials, thus enhancing the likelihood of favorable results that could quickly transition to clinical trials. From the current perspective, it is necessary to explore a greater diversity of bacterial vectors and find the best combination of implemented attenuations, generating personalized models that guarantee the maximum effectiveness in cancer therapy and vaccination.

Keywords: bacterial based vaccination; bacterial cancer; bactofection; gene therapy.

Figure 1

Main mechanisms of bactofection to induce an immune response against a codified antigen. Oral administered S. typhimurium (transformed with a certain construct) reaches the terminal ileum and infects M-cells through their type III secretion system (T3SS), then is subsequently translocated to the Peyer patches where macrophages phagocyte it. The acidic environment of the phagolysosome activates an inducible promoter within the construct, leading to the transcription of the desired genes. After bacterial lysis, the mRNA reaches the cytosol, where it is translated into protein; this exogenous protein is then processed and presented in the MHC II context to induce a strong humoral immune response against the desired antigen.

Figure 2

Bacterial and phagolysosome disruption, mRNA release, translation, antigen presentation, and T CD4+ activation mechanisms. In the transformed bacteria, the transcription of LyE and LLO lysins is activated under the phagolysosome’s acidic environment, releasing the cargo mRNA. This is followed by protein translation, proteasomal degradation, MHC II presentation, and subsequent CD4+ T cell activation. LyE transcription triggers bacterial lysis, while LLO transcription induces the formation of pores in the phagolysosome membrane, through which mRNA escapes.

Figure 3

Bacterial strains most commonly used in vaccination by percentage.

Figure 4

Percentage of bacterial strains most commonly used in cancer therapy.

Figure 5

Current level of progress in clinical trials employing bacterial vector-based anticancer treatments. Main clinical trials according to the phase and specific pathological approach.

Figure 6

Preparation Method and Loading Strategies for Ghost Vaccine Candidates with Therapeutic DNA or Drugs. LyE protein from phage PhiX174 disrupts bacterial membrane leading to intracellular content extrusion. After several washes with PBS and centrifugation cycles, the ghosts are loaded with the desired therapeutic content. Up to ~6000 therapeutic plasmids per ghost or a not specified amount of chemotherapeutic drug or prodrug is loaded in the ghost bacteria. In both cases, the cargo is not covalently attached to the inner ghost membrane.