Repolarisation of the immune-suppressive millieu of the ovarian tumour using targeted therapeutics

Khan, Adnan R. (2012) Repolarisation of the immune-suppressive millieu of the ovarian tumour using targeted therapeutics. PhD thesis, University of Nottingham.

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Abstract

Ovarian cancer is a disease which is fatal in the majority of cases. The evolution of surgery and chemotherapy over the past 30 years has resulted in improvements in overall and progression-free survival. However, the rate of relapse in ovarian cancer is very high, suggesting that current treatment strategies are ineffective. Therefore, to overcome the poor prognosis of ovarian cancer, immunotherapeutic strategies have been devised such as the use of anti-CTLA-4 antibody therapy in melanoma. The principle that the immune system can effect either cancer development or clearance has been the subject of debate for over a century. Clinical results of novel immunotherapeutic approaches that aim to exploit and enhance this immunogenicity have had mixed successes such as IL-2 therapy in renal cell carcinoma. It is clear that whilst many tumours possess antigenic component in their make-up, they do not stimulate durable and effective immune responses in vivo. This may reflect the fact that tumours develop a network of escape mechanisms to circumvent tumour-specific immunity.

Due to the ineffectual nature of current treatment options and the complexity of the tumour microenvironment a coherent stratagem needs to be composed. This thesis explores, in principle, a contemporary strategy to propagate an anti-tumour immune response within ovarian cancer by using existing drugs in combination to target three different facets of ovarian cancer immunity; Regulatory T cell (Treg) migration, poor release of the tumour associated antigen, MUC1, and reduced cytotoxic T cell (CTL) proliferation.

The migration of Regulatory T cell (Treg) to ovarian cancer is principally mediated by the CCR4-CCL22 chemokine receptor-chemokine axis. AZ1, a specific antagonist for the chemokine receptor CCR4, which is highly expressed on Treg, abrogated the migration of these cells to the chemokine. This compound did not alter Treg function suggesting that its activity was specifically against Treg migration.

In order to induce an adequate T cell response, sufficient antigen needs to be provided. Camptothecin, a classical topoisomerase inhibitor, demonstrated effective tumour cell death and release of the tumour-associated antigen, MUC1. The increase in tumour antigen release and decrease in tumour load was offset by significant immune toxicity. The incorporation of Camptothecin into a synthetic drug delivery system led to a decrease in immune toxicity while retaining the drug’s anti-tumour activity.

Finally, in order to take advantage of tumour antigen release, it would be desirable to stimulate CTL. Imiquimod, the toll-like receptor 7 agonist, widely used in basal-cell carcinoma and melanoma was able to demonstrate a potential enhancement of an anti-tumour response in three ways. Firstly, the drug enhanced the activation and antigen uptake capacity of plasmacytoid dendritic cells. It also had a direct effect on CTL themselves whilst also reducing the suppressive effect of Treg.

This thesis illustrates, in principle, the possibility that a poly-pharmaceutical approach can be taken to target ovarian cancer. It indicates that readily available compounds, when used in the correct combination, could be key in developing effective anti-cancer therapy. Future work in this area should focus on using existing chemotherapeutic and immunotherapeutic drugs in combination to illicit enhanced anti-tumour cytotoxicity. Critically, the next step in developing this strategy is to acquire suitable in vivo models. This is key as there is conflicting evidence regarding the efficacy of certain drugs in mice compared to man.

Item Type:Thesis (PhD)
Supervisors:Pritchard, D.I.
Watson, S.A.
Wilkinson, R.W.
Grabowska, A.
Uncontrolled Keywords:Cancer, Immunology, Ovarian, CCR4, Regulatory T cell, MUC1, Camptothecin, Plasmacytoid Dendritic Cell, Toll-like receptors
Faculties/Schools:UK Campuses > Faculty of Science > School of Pharmacy
ID Code:2463
Deposited By:Dr Adnan R Khan
Deposited On:14 Sep 2012 13:18
Last Modified:14 Sep 2012 13:18

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