B125
Identification of new target antigens for immunotherapy of paediatric cancers
John Anderson, Mong yong Yan, Nourredine Himoudi, Owen Williams, Martin Pule
University College London, Insitute of Child Health and Great Ormond Street Hospital, UK
A prototypic cancer antigen can be considered to have high expression in tumour cells with relatively poor expression in normal tissues. It is known that some targeted tumour antigens in melanoma are downregulated by the tumours in response to immunotherapy, and we have therefore added a functional role in oncogenesis as a requisite for tumour antigen selection. Because many paediatric embryonal tumours are characterised by expression of oncogenic developmental transcription factors we chose to target these proteins as putative new tumour antigens.
The reverse immunology approach allows the identification of antigenic peptide epitopes without a priori evidence of immunogenicity. We have applied this approach to PAX3, PAX5, MYCN and PRAME to identify new antigenic epitopes, to determine incidence of antigen specific CTL in the blood of normal blood donors and cancer patients, and to generate high avidity T cell clones for isolation of T cell receptor genes for use in adoptive transfer immunotherapy.
Peptide epitopes were successfully characterised for all four targets. Whereas rather low levels of low avidity antigen specific CTL were identified for PAX3, MYCN and PRAME, the autologous repertoire contains relatively high numbers of high avidity CTL against the PAX5 antigen. This pattern of tolerance is the opposite to that predicted on the basis of expression in normal tissues because of ongoing expression in normal B cell haemopoiesis. However using allogeneic sources of T cells to bipass tolerance through immunisation of HLA-A2 transgenic mice, it has been possible to identify higher avidity CTL for MYCN and PRAME. The T cell receptors from these CTL provide the promise of effective targeted immunotherapy for a range of childhood cancers with minimal expected toxicity.
Acknowledgements
Supported by grants from SPARKS, CRUK and Research into Childhood Cancer (RICC)
