Dissertation

Therapeutic gene transfer for malignant melanoma : augmentation of direct versus indirect tumour antigen presentation

Thirdborough, Stephen M

1998

Overview

The worldwide incidence of cutaneous malignant melanoma has risen markedly during the last two decades, and by the year 2000, it is estimated that 1 in 200 individuals in the U.K. may develop metastatic melanoma during their lifetime. Critically, the current therapeutic regimes for the treatment of metastatic melanoma have largely failed to have a significant impact on long-term-survival, prompting a search for an effective adjuvant therapy for patients with disseminated disease following surgery. The summation of these findings has culminated in the emergence of therapeutic gene transfer as a potential means of eradicating residual disease. This study sought to compare the genetic modification of melanoma cells such that they can directly present tumour-associated antigens to T-cells, with strategies designed to promote tumour antigen-presentation by dendritic cells (DC). Specifically, the human melanoma cell line A-375 was transfected to express CD80 and assessed for its capacity to activate naive T-cells and to prime specific cytotoxic T-lymphocytes (CTL). In addition, A-375 cells, transfected to express granulocyte-macrophage colony-stimulating factor and interleukin-4, were examined for their capacity to support the functional maturation of DC from the peripheral blood, with a view to performing in vitro CTL priming experiments. Rather than clarifying which strategy offered the greater potential for augmenting anti-melanoma CTL responses, the results described add further to the current uncertainties regarding the treatment of cancer by gene transfer and stress the need for caution when considering the appropriate gene(s) for transfection. They also highlight the role of melanoma-derived cytokines in mediating immunosuppression.

• Publisher: ProQuest Dissertations & Theses
• Subject: Antigens / Melanoma / Metastasis / Skin cancer