Research in Nature in October 2024 leverages evidence that bacteria “naturally home in on tumours and modulate antitumour immunity” to explore potential vaccine applications. The authors engineered a probiotic Escherichia coli Nissle 1917as an antitumour vaccination platform, revealing a promising immune response. In mouse models of advanced colorectal cancer and melanoma, the vaccine triggered the immune system to suppress the growth of primary and metastatic cancers. The team hopes that this research can advance personalised cancer vaccine approaches.
Bacteria as ideal vectors
The authors identified bacteria as “ideal vectors to augment and direct” antitumour immune responses thanks to their support of the activation of both innate and adaptive immunity. Furthermore, bacteria can be synthetically engineered with ease for “safe delivery” of immunomodulatory compounds. Although various tumour neoantigen vaccines have demonstrated “promising” clinical trial results, benefit is “limited to only a subset of patients”. Thus, programming bacteria with genetic directives to release high levels of specific tumour neoantigens offers a system for the precise instruction of neoantigen targeting in situ.
The study
The researchers developed an engineered bacterial system in probiotic Escherichia coli Nissle 1917 (EcN) to “enhance expression, delivery, and immune-targeting of arrays of tumour exonic mutation-derived epitopes”. These epitopes are “highly expressed” by tumour cells and predicted to bind major histocompatibility complex (MHC) class I and class II. The system engages several “key design elements” to enhance therapeutic use:
- Optimisation of synthetic neoantigen construct form with
- Removal of cryptic plasmids and deletion of Lon and OmpT proteases to increase neoantigen accumulation
- Increased susceptibility to phagocytosis for enhanced uptake by antigen-presenting cells (APCs) and presentation of MHC class II-restricted antigens
- Expression of listeriolysin O (LLO) to induce cytosolic entry for presentation of recombinant encoded neoantigens by MHC class I molecules and T helper 1 cell (T H1)-type immunity
- Improved safety for systemic administration due to reduced survival in the blood and biofilm formation
Through exome and transcriptome sequencing of subcutaneous CT26 tumours the researchers developed a repertoire of neoantigens, which were predicted from highly expressed tumour-specific mutations. They then endeavoured to create a microbial system that could “accommodate the production and delivery of diverse sets of neoantigens” to lymphoid tissue and the tumour microenvironment (TME).
“Synthetic neoantigen construct optimisation and genetic engineering achieved a microbial platform (EcNcΔlon/ΔompT/LLO+) capable of robust production across diverse sets of tumour neoantigens, which was attenuated in immune-resistance mechanisms, effectively taken up by and proficient in activating APCs, and able to drive potent activation of T cells specific for encoded recombinant antigens to support enhanced cellular immunity.”
Vaccine applications
The study revealed that antigen sets encompassing predicted MHC-II and MHC-II binding neoantigens mediated antitumour efficacy. Enhanced frequencies of neoantigen-specific CD4+ and CD8+ T cells were seen. Across distinct tumour models and genetic backgrounds, the antitumour effect of vaccination was “accompanied by broad modulation of the immune compartment within the TME”.
“The coordinated regulation of APCs, reduction of immunosuppressive myeloid, regulatory T and B cell populations, and activation of NK cells and CD4+ and CD8+ T cells together indicate the advantage of precisely engineered microbial platforms as next-generation antitumour vaccines that align several arms of immunity.”
Furthermore, the “unique ability” of microbial vaccines to “directly remodel” the TME could “promote synergy” across various forms of immunotherapy. Microbial neoantigen vectors locally increase neoantigens density, recruit and activate dendritic cells and CD4+ and CD8+ T cells, and reduce immunosuppressive populations and ligands within the TME. Therefore, in combination with adoptive T cell therapy (ACT), they could “oppose these resistance mechanisms and provide synergistic benefit”.
“Through extra programming of the microbial vectors and rational incorporation of other immunotherapeutics, this system may achieve reliable eradication of established solid tumours and metastases through precision cancer immunotherapy using living antitumour vaccines.”
Getting closer
Jongwon Im, PhD student at Columbia University, helped lead bacterial engineering aspects of the study, and commented on the “net effect”.
“The bacterial vaccine is able to control or eliminate the growth of advanced primary or metastatic tumours and extend survival in mouse models.”
These vaccines are personal, programmed to “direct the immune system” to target “distinct genetic mutations”, said Dr Nicholas Arpaia, associate professor of microbiology and immunology at Columbia University’s Vagelos College of Physicians and Surgeons.
“As we continue to integrate additional safety optimisations through further genetic programming, we are getting closer to the point of testing this therapy in patients.”
Dr Tal Danino, associate professor of biomedical engineering at Columbia’s School of Engineering, reflected that the time to treatment will “first depend on how long it takes to sequence the tumour” for each patient.
“Then we just need to make the bacterial strains, which can be quite fast. Bacteria can be simpler to manufacture than some other vaccine platforms.”
Another benefit of bacteria is the enabled delivery of a “higher concentration of drugs that can be tolerated when these compounds are delivered systemically throughout the entire body”, suggested Dr Arpaia.
“Here, we can confine delivery directly to the tumour and locally modulate how we’re stimulating the immune system.”
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