Ibarzo Yus, Bárbara;
(2023)
Targeting and intracellular delivery of
neoantigens for cancer immunotherapy.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The development of efficient anti-tumour vaccines remains a challenge, with only one cancer vaccine approved for their use in the clinic in the last ten years. The inefficiency of cancer vaccines could be explained by the presence of an immunosuppressive environment within tumours, that render anti-tumour responses inactive, as well as a lack of efficient in vivo strategies for antigen and adjuvant targeting and delivery into dendritic cells (DCs). Here, polymer nanoparticles (polymersomes, POs) made of poly (2- (methacryloyloxyethylphosphorylcholine)-poly(2-(diisopropylaminoethyl methacrylate) (PMPC-PDPA), are proposed as antigen carriers targeting DCs, with potential to act as anti-tumour vaccines. Using POs encapsulating ovalbumin (OVA) as antigen model, it was possible to validate in vitro their uptake by DCs and their potential to trigger antigen-specific CD8 T cell responses, without toxicity. Therapeutic immunisations performed in vivo in animals harbouring the B16-OVA melanoma model highlighted the potential of POs encapsulating OVA to delay tumour growth. This correlated with enhanced CD8 T cell infiltration in the tumour bed, expressing exhaustion-related receptors. Approaches combining PO vaccination and checkpoint inhibitors enhanced anti-tumour responses and delayed tumour growth rates further. In addition, the route of PO administration at the time of immunisation demonstrated influence over disease outcome, likely due to differential targeting of lymphoid organs and DCs. These differences were also present in animals harbouring a colorectal MC38 model following immunisations with an MC-38 derived neoantigen. Altogether, this study proves the possibility to enhance and shape anti-tumour responses utilising POs as cancer vaccine carriers, outperforming conventional and nanoparticle-free cancer vaccines.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Targeting and intracellular delivery of neoantigens for cancer immunotherapy |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10174730 |
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