Abstract 2402: Stimulation of high avidity T cell responses are an essential pre-requisite for a cancer vaccine
Authors: Durrant Lindy G. , Pudney Victoria , Gunn Barbra , Spendlove Ian , Metheringham Rachael L. 
Published: February 2011

Abstract
Stimulation of high avidity T cell responses are an essential pre-requisite for a cancer vaccine.
High avidity T cell responses, or the ability of a T cell to respond to low doses of cognate MHC: peptide, has been shown to be important in both anti-viral and anti-tumour responses. However it has been more difficult to find vaccination approaches that stimulate high avidity T cell responses to self antigens in vivo. We have shown that immunising with a DNA vaccine, encoding a CTL epitope from a self antigen within the CDR of an antibody, induces a higher avidity response compared to the same epitope immunised as a peptide with MPL adjuvant. Our previous studies have shown that this high avidity response in generated by a combination of direct presentation and cross presentation via the high affinity Fc receptor, CD64. This high avidity T cell response is maintained into memory and causes rejection of established B16 tumours. More recently spectratyping has revealed that the high avidity responses were polyclonal whereas the peptide induced low avidity responses were due to stimulation of only two clonotypes (bi-clonal). If the polyclonal high avidity T cells are grown ex vivo in high doses of peptide (10µM) it is modulated to a low avidity bi-clonal response similar to the CD8 response stimulated in vivo with peptide. High dose peptide stimulation of the high avidity response resulted in high levels of apoptosis, high level expression of PD-1 and CD8 cells which became exhausted, failing to kill tumour cells. In contrast if the high avidity T cells are maintained in low dose peptide (10nM or 10pM), avidity is maintained and the cells efficiently kill tumour cells, secrete γIFN, TNFα and IL-2, proliferate, express low levels of PD-1 and do not undergoing apoptosis. Similar results have been obtained in vivo as if animals induced to produce high avidity responses, were then challenged with high dose peptide the high avidity response was lost. This has implications for vaccine therapy as high dose vaccines may either be inducing low avidity T cells that fail to control tumour growth and or killing a pre-existing high avidity response. This would have detrimental effects on patient survival, as has been shown with recent phase III vaccine trials. In contrast effective vaccination with epitopes encoded with an antibody molecule can induce high avidity T cells even if in the presence of a low avidity memory response. These results show that effective vaccination can lead to a polyclonal high avidity memory response that can efficiently kill tumours and result in regression of bulky disease even in the face of pre-existing low avidity memory responses. This vaccine is scheduled to enter clinical trials in April 2010 to determine if high avidity T cells can be induced in cancer patients.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2402.