Oral anti-cancer vaccine? It’s moving towards reality

The working principle of the oral vaccine system based on “bacterial robot” and its evaluation of anti-tumor immune effect. (Provided by respondents)

As you may recall, as a child, you were asked to take “sugar pills” as a vaccine against polio. This “sweet” experience is one of the most successful vaccination strategies in human history. We have never stopped imagining that we will drive away the evil “tumor king” through oral vaccination.

Thanks to the rapid development of technologies in the fields of immunology, genetic engineering, bioinformatics, etc., people can quickly obtain antigen information in tumor cells, and tumor vaccines have also found a way to achieve it.

Recently, the Team of Nie Guangjun of the National Center for Nanoscience and the team of Zhao Xiao collaborated to publish a paper in the journal Nature-Biomedical Engineering, using genetic engineering to transform bacteria into a “bacterial robot” that can work in vivo, and controlling these “bacterial robots” to use the outer membrane vesicle (OMV) with tumor antigens in the intestine by oral “sugar pills” as tumor vaccines to stimulate the body’s antitumor immune response to fight various tumors.

Discover the ideal oral oncology vaccine

In the increasingly strong call for precision treatment, tumor vaccine research made important progress in 2017. As a personalized tumor immunotherapy, tumor vaccines use tumor antigens produced by genetic mutations to stimulate the body’s immune system, produce tumor cell-specific immune responses, and then kill tumor cells.

There are currently a number of tumor vaccines in clinical trials worldwide, but most of them are intramuscular or subcutaneously injected, where immune stimulation is limited to a limited number of drainage lymph nodes. Because antigen-presenting cells (APCs) have a limited distribution within muscle and subcutaneous tissue, injectable tumor vaccines also require adjuvant to improve immunogenicity.

As a result, the intestine, which contains about 70% of the body’s immune cells, has become a new focus for researchers, who hope to develop export-style tumor vaccines that can be safer, more economical, and more patient compliance.

In recent years, liposomes, polymer nanoparticles, etc. have developed rapidly as vaccine delivery carriers, but the main application scenario is the vaccine carrier for injection. The ideal oral oncology vaccine must tolerate the gastrointestinal environment to reach the gut and overcome the intestinal epithelial barrier, interacting with immune cells in the rich intestinal layer.

In this study, the Nie Guangjun/Zhao Xiao team genetically engineered E. coli, one of the most abundant symbiotic bacteria in the intestine, to develop an oral tumor vaccine based on “bacterial robots”, which can achieve controllable OMV carrying tumor antigens in the intestine after oral administration.

As a natural medium for the interaction of the intestinal flora with the body’s immune system, OMV can carry tumor antigens effectively across the intestinal epithelial barrier, be recognized by immune cells in the intrinsic layer, activate the tumor antigen-specific immune response, thereby significantly inhibiting tumor growth, limiting tumor metastasis, and exerting long-term protective effects.

The mouse model experiment was a breakthrough

In recent years, the use of genetically engineered microorganisms to deliver therapeutic drugs or use themselves as therapeutic agents has received increasing attention.

Previous studies have demonstrated that oral administration of genetically engineered bacteria or modified probiotics can identify colon cancer tissue in the gut and enable therapeutic agents to be delivered locally, thereby promoting tumor regression. This genetically engineered bacterium can treat certain diseases, such as inflammatory bowel disease and metabolic disorders, by secreting active ingredients in situ in the intestine, and there have been some previous reports of oral OMV to prevent shigellosis or intestinal inflammation.

However, the specific mechanisms of OMV function and metabolism in humans are unclear, and there are few reports of genetically engineered bacteria secreting functional OMV in the intestine to treat disease.

In this study, in order to control the behavior of the “bacterial robot” in the intestine, the research team introduced an arabinose (Ara) inducible promoter to control the expression of tumor antigens and the secretion of the purpose OMV – that is, only in the presence of arabinose, the bacterial nanorobots are induced to express tumor antigens, otherwise the expression is in a closed state, thus avoiding immune tolerance caused by continuous stimulation of the antigens.

Mouse model experiments have shown that oral administration of the above genetically engineered bacteria and the inducer arabinose can achieve controlled production of tumor antigen-carrying outer membrane vesicles in the in situ in the intestine.

According to the Nature-Biomedical Engineering reviewer, “This is a proof-of-concept study with sufficient novelty that can also be tried in the future in the field of infectious disease vaccines.” ”

OMV has great potential

Nie Guangjun introduced that tumor vaccines usually need to improve immunogenicity through adjuvants, and as a natural nanoparticle secreted by bacteria, OMV is rich in bacterial-derived substances, which can effectively activate natural immune signaling pathways, which itself has an adjuvant effect, so as to achieve the combination of tumor vaccines and adjuvants into one, and OMV as a vaccine carrier, in addition to being used to display and deliver polypeptide antigens, can also deliver messenger ribonucleic acid (mRNA) antigens, and then develop mRNA tumor vaccines.

In April 2021, the Nie Guangjun/Zhao Xiao team published another collaborative work in Nature Communications, in which they established an OMV-based “plug and play” type personalized tumor vaccine platform technology that can quickly display peptide tumor antigens and achieve efficient delivery and immune stimulation. This is the first time that OMV has been applied to an injectable therapeutic tumor vaccine, which is equivalent to equipping the vaccine with a “chariot” that accurately “strikes” tumor cells.

The two teams have long been committed to the design and development of different types of vaccine vectors using nanotechnology and biotechnology.

In March this year, they continued to collaborate in the publication of a paper in Advanced Materials, exploring for the first time the use of OMV as an mRNA vaccine delivery vector, that is, the modification of RNA-binding proteins on the surface of OMV through genetic engineering to achieve mRNA delivery; in order to enhance delivery efficiency, they further functionalized the OMV vector so that it can effectively bind mRNA antigens and deliver them to antigen-delivery cells for efficient expression.

The results showed that the OMV-mRNA tumor vaccine could significantly inhibit the progression of melanoma in mice, resulting in complete tumor regression in 37.5% of the mouse models of colorectal cancer, and could induce long-term immune memory, which could still protect the mice from tumor attack after 60 days of vaccination.

Their series of groundbreaking studies open up broader prospects for therapeutic applications based on genetically engineered microbes. Zhao Xiao told China Science Daily that in future research, it will continue to explore OMV-based tumor vaccines in depth and work on the translation and clinical application of these technologies. (Source: China Science Daily Zhang Nan)

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