Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.808321
Title: Drug-device development : cancer immunotherapy with therapeutic, ultrasound-mediated delivery
Author: Katti, Prateek S.
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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Abstract:
Tumour and tumour microenvironment exploitation of immunologic checkpoints like PDL1 can enable immune evasion. Recent advances in oncology, have brought forward antibody drugs, such as anti-PD-L1, capable of blocking and/or mediating the eradication of cells that express PD-L1. Despite promise across a wide range of indications, clinically such agents meaningfully extend survival only in a fraction of patients treated. Immature, heterogenous blood vessels, elevated interstitial pressures, and stromal barriers severely limit the accumulation and extravasation of drugs within the tumour microenvironment. We hypothesize that the physical size of antibody therapeutics, such as antiPD-L1, compounded by delivery barriers could be a factor limiting their efficacy. Recently, submicron cavitation nucleation agents, sonosensitive particles (SSPs), activated by focused ultrasound have been shown to improve the delivery of large, anti-cancer therapeutics via microstreaming-mediated transport. Our aim was to pre-clinically investigate whether systemically-dosed anti-PD-L1 followed by SSPs and the application of focused ultrasound could improve the intratumoural delivery and therapeutic efficacy of anti-PD-L1. Efficacy studies revealed that pairing anti-PD-L1 with ultrasound-mediated cavitation can significantly extend median survival time. Cavitation was also found to enhance the intratumoural accumulation of anti-PD-L1 and three other antibodies. Further, the binding intensity and distribution of anti-PD-L1 improved in cavitation-treated tumours. Immunological analysis suggests that anti-PD-L1 paired with cavitation enables the innate and adaptive immune system to leverage the modest cavitation-induced inflammation and improved anti-PDL1 delivery to facilitate tumour attack. Taken in a broader context, this pre-clinical work suggests that ultrasound-mediated cavitation warrants further investigation as viable tool to improve drug delivery clinically.
Supervisor: Hester, Joanna ; Coussios, Constantin-Cassios ; Carlisle, Robert Crispin ; Lobley, Kathryn Sponsor: NIH
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.808321  DOI: Not available
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