[Frontier Science Popularization] Anti-tumor Bacteria Represented by Salmonella-Related Progress and Prospect of Bacterial Anti-tumor Therapy (IV)

[Frontier Science Popularization] Anti-tumor Bacteria Represented by Salmonella-Related Progress and Prospect of Bacterial Anti-tumor Therapy (IV)

1. About Salmonella

is the most in-depth study of the bacterial vector, Salmonella can selectively grow and enrich in tumor tissue, in tumor tissue and normal tissue colonization ratio of more than 1000 times. It is a facultative anaerobic intracellular bacterium that is easy to be genetically modified. It has flagella and can obtain nutrients such as ribose or amino acids through exercise. These nutrients are usually found in hypoxic and necrotic tumors. Therefore, these properties allow it to colonize large tumors in the surrounding hypoxic environment and small tumors caused by metastasis.
As an intracellular pathogen, studies have shown that the anti-tumor mechanism of Salmonella is due to the induction of apoptosis and autophagy in tumor cells. Tumor cells infected with Salmonella can maintain pathogen detection and signal transduction mechanisms in the inflammatory response, thereby increasing the infiltration of activated macrophages and neutrophils into the tumor and enhancing the anti-tumor response. Salmonella into solid tumors will upregulate the production and release of TNF-α and inhibit tumor angiogenesis. The genome of Salmonella is relatively easy to manipulate, which increases the likelihood that it will be used to create conditional mutants or gene expression delivery vectors.
In the anti-tumor study of Salmonella, the researchers found that (1) Salmonella can reduce tumor metastasis, this is because Salmonella infection reduces the level of VEGF in tumor tissue and affects angiogenesis. (2) Salmonella through the recruitment of immune cells to induce host anti-tumor immune response, killing the primary site of tumor cells, thereby preventing the formation of tumor metastasis. (3) Salmonella enhanced tumor chemotherapy sensitivity. Salmonella can enhance the gap junction intercellular communication, change the permeability of the cell membrane, and re-sensitize the drug-resistant tumor cells. (4) Salmonella combination therapy further promoted tumor regression. The hypoxic targeting capacity of Salmonella may also be used in combination with photothermal therapy.
Salmonella and others have the ability to carry plasmids in cells and localize to tumor tissues in mouse models, which are considered to be potential vaccine vectors and gene delivery vehicles. In order to obtain better tumor treatment effect, in the past ten years, we have been trying to use attenuated Salmonella as a vector to target tumor and deliver a variety of therapeutic molecules. Attenuated Salmonella can be used to directly express the coding gene of the tumor therapeutic molecule through its own prokaryotic expression system and then presented to the tumor cells; or attenuated Salmonella can be used to present the coding gene of the tumor therapeutic molecule into the tumor cells, so that the eukaryotic expression system of the tumor cells themselves can be used for gene expression. The expression of these therapeutic molecular genes can play an anti-tumor effect in the tumor, and can produce a synergistic anti-tumor effect with Salmonella without affecting the growth and reproduction of Salmonella.
Salmonella-related clinical trials are currently in phase I. The first strain to be used in clinical trials was VNP20009,VNP20009 showed good tumor colonization ability in clinical trials, but did not have effective tumor treatment effect. Other modified Salmonella strains include A1-R and & Delta;ppGpp, etc. have certain preclinical research results. Articles report & Delta;ppGpp has good targeting ability in mouse colon cancer model, and modified to express cytotoxic proteins, showing good therapeutic effect in mouse orthotopic tumor model and lung metastasis model. Other major bacteria are shown in Table 1 below.

Table 1 Comparison of major bacteria

2. Clinical application prospect of bacterial anti-tumor therapy

bacterial therapies work in tumors include:

a) Bacteria act as anti-tumor agents by enhancing human immunity

bacteria interact with the host as pathogens or normal flora to enhance the host's immune system in different ways. Can activate the inflammasome pathway and induce the production of T lymphocytes.? ppGpp Salmonella typhimurium strains activate the inflammasome pathway by disrupting signals released by tumor cells. When E. coli invades the host, it stimulates the initiation of host defense mechanisms and activates the antitumor activity of T lymphocytes.

B) Bacteria act as antineoplastic agents by releasing substances

bacteria, such as enzymes, can inhibit the growth of tumors. Several experimental studies have found the therapeutic potential of different substances released by bacteria for the treatment of tumor cell lines. Bacteriocins secreted by Escherichia coli have antitumor activity against a variety of human tumor cell lines in vitro. Bacteriocins produced by Pseudomonas aeruginosa have shown antitumor activity. Phenazine 1,6-dicarboxylic acid produced by bacteria shows a cytotoxic effect on tumor cells of many origins.

c) Bacterial use of biofilms as anti-tumor agents

biofilm is a primitive multicellular life form that provides bacteria with the strength of resistance to antibiotics and host defense mechanisms. Salmonella typhimurium and some other pathogens can cause severe bleeding within tumors, and once the bleeding response is activated, it induces the production of T cells, which is very important in the process of biofilm induction. Although the pathogenesis of biofilms and their protective effects allow bacteria to escape the host defense system, recent findings have revealed the potential capacity and efficacy of biofilms in the treatment of malignant tumors. Antitumor drugs induce biofilm formation during treatment of malignant tumors, resulting in metastasis dispersion. Similarly, the formation of bacterial biofilms on tumor cells during the SOS response leads to the disruption of metastasis. Thus, bacterial biofilms show potential usefulness in the treatment of malignancies.

d) Bacteria as carriers of therapeutic agents for malignant tumors

, because bacteria can target primary tumors, they can serve as carriers for malignant tumor therapeutics. The growth and metastasis of solid tumors depend on the formation of new blood vessels, so blocking tumor angiogenesis is a strategy for the treatment of solid tumors. After comparing several bacteria, the researchers found that the facultative anaerobic bacterium Salmonella is a particularly good bacterial carrier due to its higher motility and accumulation at tumor sites.

3. Bacterial therapy versus other cancer therapies
Traditional tumor therapy, including surgical resection, chemotherapy, radiotherapy, has a strong lethality to the early tumor, patients expect good, but for the middle and late patients is usually not effective, coupled with the traditional therapy of high invasiveness and wide impact of adverse reactions, the position of this kind of therapy in the treatment of middle and late patients is gradually replaced by new immunotherapy. New therapies cover several broad categories, including tumor immune antibody drugs, cell gene therapy, oncolytic virus therapy, bacterial therapy, etc. Bacterial therapy is mainly based on stimulating the immune response produced by the body and the characteristics of some bacteria that can target into the growth and reproduction of solid tumors. By displaying tumor targeting molecules or knocking out some genes, the tumor targeting and biocompatibility of bacteria can be increased; the expression of cytotoxic proteins and immune factors can effectively inhibit the growth of tumors. Bacteria combined with chemotherapy, radiotherapy and immunotherapy have shown high anti-tumor effect and low toxic side effects.

Table 2 Comparison of advantages and disadvantages of bacterial therapy and other cancer therapies

4, Global Bacterial Clinical Trials Analysis
In the global clinical trials of using bacteria to treat tumors, Listeria monocytogenes, Salmonella and probiotics are the main causes, accounting for 40%,16% and 22% respectively, as shown in Figure 1 below. The types of bacteria used to treat malignant tumors are diverse, including Streptococcus, Bacillus, Klebsiella, etc. Gram-positive bacteria accounted for more than half of the clinical trials, reaching 79%.

Figure 1 Global bacterial therapeutic product clinical trial share layout.

Note: The above main contents are taken from the research report of Yaodu.