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Investigation of the activation of tumour-specific immune responses by gene therapy strategies using a model tumour antigen

Salman, Asmaa Mohamed Mohamed (2012)
Ph.D. thesis, University of Birmingham.

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Abstract

Gene directed enzyme prodrug therapy using E.coli the enzyme nitroreductase (NR) to activate the prodrug CB1954, is being developed as an attractive targeted chemotherapy for eradication of localized tumours. In addition to direct killing of NR-expressing tumour cells and potentially also their immediate neighbours via local spread of the activated prodrug, the consequent release of tumour antigens from dying tumour cells has the potential to induce antitumour immune responses. The present study investigates the capacity of NR/CB1954-mediated tumour cell death to activate CD8\(^+\) T cell responses using ovalbumin (OVA), as a model tumour antigen. The transgenic adenocarcinoma mouse prostate tumour cell line (Tramp-C1) was modified to stably express the therapeutic NR gene together OVA. These modified tumour cells were used to seed tumours in mice and OVA-specific T cell responses to gene therapy were investigated. Treatment of mice bearing NR-expressing tumours with CB1954 enhanced expansion of endogenous OVA-specific CD8\(^+\) T cells and marginally enhanced OVA-specific cytotoxic T lymphocyte (CTL) activity, however long-term CD8\(^+\) T cell dependent immunity was insignificant. The possibility of enhancing NR/CB1954-mediated long-term antitumour immune responses by combining with other immunogene therapies namely, 4-1BB costimulatory ligand (4-1BBL) or granulocyte macrophage colony stimulation factor (GM-CSF) was further explored. These combined therapies notably increased the frequency of memory OVA-specific CD8\(^+\) T cell and CTL response in some lymphoid tissue relative to NR/CB1954 monotherapy. One of the obstacles to cancer immunotherapy is the development of T cell anergy early in the course of tumour progression, therefore it was of interest to investigate the potential of NR/CB1954 and 4-1BBL combined tumour therapy to reverse CD8\(^+\) T cells anergy in vivo. This study describes preliminary results showing the effect of this combined therapy on the proliferative and functional responsiveness of anergic CD8\(^+\) T cells. In conclusion, these findings indicate that NR/CB1954-mediated tumour cell death is a weakly immunogenic process that facilitates short-term antitumour CD8\(^+\) T cell responses. Combining NR/CB1954 with intratumoural GM-CSF or 4-1BBL immunotherapy can enhance the frequency and effector function of memory tumour antigen-specific CD8\(^+\) T cells; and thus has the potential to provide long-term antitumour immunity.

Type of Work:Ph.D. thesis.
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Cancer Sciences
Subjects:QR Microbiology
QR180 Immunology
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:3532
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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