Discussion

Adoptive T cell therapy (ACT) with gene-modified T cells is emerging as a promising strategy for the treatment of many forms of cancer. Unlike antibody based therapies, T cell receptors (TCRs)have access to the larger pool of intracellular antigens presented on the cell surface as short peptides bound to human leukocyte antigen (HLA). The success of ACT depends on comprehensive and robust safety testing to mitigate the risks posed by target presentation on healthy tissue and off target cross-reactivity to a homologous peptide. We have developed methods to produce precision-engineered TCRs with optimal affinity for a given tumour antigen to address the problem of low T cell antigen affinity imposed by thymic selection. Fine-tuning each antigen-specific TCR is essential to ensure the appropriate balance between functionality and specificity. A TCR has been developed to target the HLA-A2 restricted NY-ESO-1 cancer-testis antigen that is overexpressed in a wide range of cancer types. Preliminary results from a pilot clinical trial in synovial sarcoma patients indicate responses in four of five patients, including one complete response. Extensive flow cytometric analysis of gene-modified T cells isolated from trial patients show that they possess phenotypic characteristics in line with a typical T cell immune response.