Rusakiewicz, Sylvie; (2005) Development of epitope-based immunotherapy for the treatment of chronic myeloid leukaemia. Doctoral thesis , UCL (University College London).

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Abstract

Haematopoietic stem cell transplantation, one of the major treatments for Chronic Myeloid Leukaemia (CML), provides an allogeneic Graft-versus-Leukaemia (GvL) effect mediated by the donor T cells infused with the graft. The antigens recognized by these T cells are not yet identified. One candidate antigen is the CML specific BCR7ABL oncogene. The aim of this thesis is to investigate immunotherapeutic strategies for the treatment of CML targeted to BCR/ABL epitopes. We characterised BCR/ABL derived peptides that are naturally processed and presented on the surface of CML cells in the context of both HLA-A0301 and HLA-B0801 molecules. In order to screen for the presence of BCR/ABL specific T cells in CML patient samples, we generated HLA tetramer complexes, refolded with the appropriate BCR/ABL peptide. We detected the presence of low frequency (1%) BCR/ABL specific CDS+ T cells circulating in the peripheral blood of CML patients. The expansion of these BCR/ABL specific CTLs from healthy donors and CML patients was attempted using a number of different protocols, including peptide-pulsed dendritic cells. We generated leukaemia specific CTLs in some cases from healthy donors but not from patients. It was however possible in both groups to generate responses to viral antigens. We therefore investigated BCR/ABL immunogenicity, comparing CML patient responses to BCR/ABL antigens with other GvL associated tumour antigens. To circumvent a potential Antigen Presenting Cell (APC) deficiency in CML patients, we generated a standardized and unlimited source of artificial soluble Antigen-Presenting Complexes by cross-linking BCR-ABL HLA/peptide monomers with costimulatory molecules. These sAPCs successfully generated functional CDS BCR/ABL T cells from both healthy individuals and CML patients. The data presented here demonstrates the feasibility of BCR/ABL based adoptive T cell immunotherapy for CML patients, at least in the context of HLA-A0301.

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