TCRabX · Structural basis for the therapeutic efficiency of optimal-affinity T cell receptors

Structural basis for the therapeutic efficiency of optimal-affinity T cell receptors

A malignant solid tumour is a life-threatening disease that is difficult to cure. Currently, solid tumours are treated with classical therapies such as surgery, chemotherapy and radiation. Adoptive T cell therapy represents an alternative treatment method that can attack the tumours very specifically. Many tumour patients already benefit from adoptive T cell therapy, but a large proportion of patients also experience severe side effects and the therapy does not work. The prerequisite for the high specificity of the treatment is that the T cells used are equipped with high-affinity T cell receptors (TCRs). These should only recognize the tumour but not recognize other tissue, and they should eliminate the tumour efficiently. Since tumour antigens are mostly endogenous and are therefore self-antigens, it is difficult to isolate high-affinity TCRs from patients or healthy volunteers. In a new approach, human TCRs have been isolated from humanized mice in the last decade. The mice have a human T cell repertoire and are antigen-negative with respect to human tumour antigens. Under these circumstances, it is possible to obtain tumour-specific TCRs with high peptide sensitivity, suitable for therapy. During the isolation of tumour-specific TCRs, the immunological aspects of the TCRs are investigated. The main objective of such initial tests is to determine high effectiveness of the TCRs and to avoid detection of non-malignant somatic cells. There is little information available to date on how a mouse-derived TCR with high peptide sensitivity differs from a human-derived TCR with lower peptide sensitivity with regard to biochemical parameters. Experimental data are required to relate the immunological parameter of peptide sensitivity to biochemical parameters such as affinity or to structural information regarding the interaction of the TCR with its target, the peptide-human leukocyte antigen complexes (pHLA). The objective of this project was to compare the biochemical properties, in particular the parameters of binding of mouse-derived TCRs or human-derived TCRs to the respective pHLA. The methods applied were surface plasmon resonance measurements of TCR-pHLA binding as well as X-ray structural analysis of pHLA molecules and TCR-pHLA complexes. The mouse-derived TCRs and human-derived TCRs showed different affinities for the pHLA. The TCRs also differed in their kinetics of binding to pHLA. In the future, the findings will help to better understand the mode of action of optimal affinity therapeutic TCRs. This information is of interest not only for basic research but also for partners in industry. The data will support both the future development and optimization of existing adoptive T cell therapies.

Data: CORDIS, © European Union