Evaluating immunovirotherapies in ex vivo, patient derived ovarian cancer models

Naskretski, Adam 2024. Evaluating immunovirotherapies in ex vivo, patient derived ovarian cancer models. MD Thesis, Cardiff University. Item availability restricted.

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Abstract

Ovarian cancer is a complex gynaecological malignancy, presenting a profound management challenge for patients and clinicians. Despite advancements in treatment options, it remains an incurable disease with poor prognosis and high recurrence rate. Immunotherapy revolutionised the management of many cancers in recent years, however, less so in ovarian cancer. With a new, targeted, and improved delivery method, there is potential to introduce novel therapies for advanced and recurrent ovarian cancer. Oncolytic viral vectors possess many advantageous properties to deliver therapeutic agents, with high specificity and the ability to penetrate the tumour microenvironment as well as independently kill tumour cells and potentiate the immune response against cancer. Ad5NULLA20 is a highly engineered viral vector with multiple modifications, programmed to enter cells via the 6 integrin, shown to be overexpressed in ovarian cancer. The therapeutic potential of oncolytic viruses can be further enhanced by incorporating immunotherapy agents into the viral genome. Bispecific T-cell engagers and Natural Killer engagers are novel immunotherapy agents characterised by their unique structure consisting of two antigen binding areas. This allows for simultaneous binding of patient’s own immune cells with targeted cancer cells via ovarian cancer specific folate receptor alpha (FOLR1) resulting in immune mediated killing of tumour cells. This thesis aimed to evaluate viral vectors as potential treatment for ovarian cancer. The main goal was to design, develop and test Ad5NULL-A20 based immunovirotherapy expressing bispecific T-cell and Natural Killer cell engager constructs. Of the four proposed constructs, viral vector expressing CD3:FOLR1 transgene was shown to be effective and resulted in secretion of a functional bispecific T-cell engager. In vitro results show promise in activating the immune response and induce cell-mediated tumour cell killing. However, testing on ascites derived models did not show significant tumour killing therefore this approach, and optimisation of ovarian cancer models, need further evaluation.

Item Type:	Thesis (MD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Funders:	South Wales Gynaecological Cancer Fund
Date of First Compliant Deposit:	9 May 2025
Last Modified:	09 May 2025 15:49
URI:	https://orca.cardiff.ac.uk/id/eprint/178184

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