Prospects for immunotherapy of malignant disease

Abstract

The majority of T cell-recognized tumour antigens in humans are encoded by genes that are also present in normal tissues. Low levels of gene expression in normal cells can lead to the inactivation of high-avidity T cells by immunological tolerance mechanisms. As a consequence, low-avidity T cell responses in patients are often inadequate in providing tumour protection. Recently, several technologies have been developed to overcome tolerance, allowing the isolation of high-affinity, HLA-restricted receptors specific for tumour-associated peptide epitopes. Furthermore, transfer of HLA-restricted antigen receptors provides an opportunity to empower patient T cells with new tumour-reactive specificities that cannot be retrieved from the autologous T cell repertoire.

Fig. 1

Novel approaches for the generation of high-avidity CTL specific for tumour-associated antigens. Overview of four recently developed technologies to isolate high-affinity receptors specific for HLA class I presented peptide epitopes (HLA-A2 is shown because it is one of the most frequent class I alleles in humans). (a) and (b) take advantage of the TCR repertoire of healthy individuals or transgenic mice that are not tolerant to A2-presented peptide epitopes of tumour-associated antigens (TAA); (c) and (d) take advantage of in vitro mutagenesis and selection of high affinity TCRs (c) or high-affinity single chain antibodies specific for the peptide/HLA combination. (e) Strategies to transfer high avidity HLA-restricted receptors into patient T cells or stem cells to produce tumour-reactive T cells.