4 research outputs found
Activity of oncolytic vaccinia virus vectors in ovarian cancer.
PhDOncolytic vaccinia virus has great potential in the treatment of cancer and two engineered
strains have entered clinical trials. As the advent for oncolytic vaccinia virus as an approved
therapy beckons, it is critical to consider some of the barriers that may hinder this progress.
These include suboptimal delivery of the virus to tumour sites, incomplete destruction of the
tumour mass, and a lack of full understanding of the way in which oncolytic vaccinia kills its
target cells. This thesis attempts to address these issues, with a particular focus on ovarian
cancer.
As ovarian cancer is generally restricted to the peritoneal cavity, intraperitoneal delivery may
be preferable over intravenous delivery. Here, it is shown that Lister-dTK, an engineered
vaccinia strain, is able to selectively replicate in ovarian tumours, including metastases to the
liver following intraperitoneal delivery. To determine whether Lister-dTK could potentially
be used in combination with current therapies for ovarian cancer, the effect of cisplatin and
Lister-dTK together was assessed in vitro but showed no improvement in overall cell death.
In an attempt to further improve the anti-tumour efficacy of Lister-dTK, the extracellular
matrix protein (ECM) decorin was expressed from the virus. Decorin interacts with various
signalling pathways and is proposed to enhance virus spread. However, abrogation of EGFR
and TGFβ signalling could not be demonstrated in vitro, nor could improved virus spread. In
an intraperitoneal model of ovarian cancer, Lister-mDCN did not demonstrate enhanced
efficacy over a control virus.
To determine the mechanisms of ovarian cancer cell death induced by Lister-dTK, the roles of
apoptosis, autophagy and necrosis were investigated. Whilst some features of both apoptosis
and autophagy were observed, inhibition of these pathways did not attenuate Lister-dTK. It is
proposed that necrosis is the primary cause of cell death but that this process may occur in a
regulated manner
Synergistic chemo-immunotherapy of epithelial ovarian cancer using ErbB re-targeted T-cells combined with carboplatin.
Abstract
Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, underscoring the need for better therapies. Adoptive immunotherapy using genetically targeted T cells represents a promising new treatment for hematologic malignancies. However, solid tumors impose additional obstacles, including the lack of suitable targets for safe systemic therapy and the need to achieve effective T cell homing to sites of disease. Because EOC undergoes transcœlomic metastasis, both of these challenges may be circumvented by T cell administration to the peritoneal cavity. In this study, we describe such an immunotherapeutic approach for EOC, in which human T cells were targeted against the extended ErbB family, using a chimeric Ag receptor named T1E28z. T1E28z was coexpressed with a chimeric cytokine receptor named 4αβ (combination termed T4), enabling the selective ex vivo expansion of engineered T cells using IL-4. Unlike control T cells, T4+ T cells from healthy donors and patients with EOC were activated by and destroyed ErbB+ EOC tumor cell lines and autologous tumor cultures. In vivo antitumor activity was demonstrated in mice bearing established luciferase-expressing SKOV-3 EOC xenografts. Tumor regression was accompanied by mild toxicity, manifested by weight loss. Although efficacy was transient, therapeutic response could be prolonged by repeated T cell administration. Furthermore, prior treatment with noncytotoxic doses of carboplatin sensitized SKOV-3 tumors to T4 immunotherapy, promoting enhanced disease regression using lower doses of T4+ T cells. By combining these approaches, we demonstrate that repeated administration of carboplatin followed by T4+ T cells achieved optimum therapeutic benefit in the absence of significant toxicity, even in mice with advanced tumor burdens.</jats:p