Firth, Jack; (2024) Exploring The Immunogenicity of Bacterial Outer Membrane Vesicles and Their Use in Cancer Immunotherapy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Ubiquitously produced by Gram-negative bacteria to interact with their environment, outer membrane vesicles (OMVs) are immunogenic nanoparticles shed from the bacterial cell envelope. Evidence suggests the immune activation elicited by OMVs propagates a potent anti-tumour response. However, the cellular mechanisms underlying this are yet to be fully characterised. Herein, we sought to investigate OMV-mediated immune interactions, elucidating key cells able to be leveraged in the context of a cancer immunotherapy, as well as exploring the presence of such cells within the tumour microenvironment. We also strove to engineer a tumour targeting OMV, attempting to improve future translation of preclinical efficacy into a clinical context. Within this research, OMVs were shown to induce a robust inflammatory response, along with broad activation of cytotoxic lymphocytes. Vγ9Vδ2 T cells proliferated to dominate the immune population, and subsequently demonstrated oncolytic capabilities against both epithelial and haematological cancer types. Finally, development of a tumour-targeting construct was achieved by the expression of an anti-HER2 DARPin binding protein. Whilst the construct successfully exhibited an ability to bind soluble HER2, mass internalisation of OMVs into various cell types regardless of targeting moiety or presence of the target antigen, pose significant questions as to the clinical specificity and safety of such a system. Ultimately this research identified Vγ9Vδ2 T cells as a significant oncolytic mediator of the OMV anti-tumour response. We further revealed considerable limitations which remain in actively targeting the tumour site. Consequently, we hope this research can be used to improve OMV immunotherapies, facilitating the development of treatments that can provide meaningful benefit to patients.

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