Developing peptide vaccines for breast cancer

The complex and heterogeneous nature of breast cancer presents significant challenges for many conventional cancer therapies. Immunotherapy has the potential to provide a more potent, less invasive and less toxic approach to breast cancer treatment, with several successes already evident in the treatment of metastatic melanoma. Three recently described tumour-associated antigens (TAAs); (1) NY-BR-1, (2) cadherin-3/P-cadherin (CDH3), and (3) bone marrow stromal cell antigen-2 (BST-2), have been implicated as candidates for breast cancer vaccination strategies. However, peptide vaccines that are designed using wild-type (WT) sequences of these proteins are likely to elicit suboptimal T-cell responses in patients. This is generally attributable to the low affinity of thymically-selected Tcell receptors (TCRs) for “self” TAAs. Here I describe a method for enhancing the immunogenicity of these three HLA-A*0201 (HLA-A2)-restricted breast cancer epitopes. Firstly, αβ CD8+ T-cell clones were generated against each of the epitopes using three different approaches; (i) T-cell lines and (ii) T-cell libraries (Chapter 3),and (iii) tumour-infiltrating lymphocytes (TILs) (Chapter 4), and the breast cancer reactivity of these clones confirmed in vitro. Then, using a positional scanning synthetic combinatorial library (PS-SCL), altered peptide ligands (APLs) were designed for each of the clones (Chapter 5). These APLs were shown to be up to 100,000-fold more potent than the respective WT epitopes. Preliminary “proof-ofconcept” CD8+ T-cell priming experiments on healthy HLA-A2+ donors were then used to establish whether a chosen BST-2 APL was capable of activating superior breast cancer specific T-cell populations in vitro (Chapter 6). From these preliminary investigations, it was found that the BST-2 APL was capable of generating a T-cell response of greater magnitude, and that was also better able to kill breast cancer cells when compared to the corresponding BST-2 WT peptide. Together, these experiments illustrate the potential use of APLs for the development of a highly effective prophylactic or therapeutic peptide vaccine for breast cancer