Adoptive transfer of T cell receptor (TCR)-engineered T cells is a promising approach in cancer therapy but needs improvement for effective treatment of solid tumours. So far clinical approaches have focussed on CD8 T cells because of their cytotoxic function. However, the importance of CD4 T cells to induce tumour regression by giving essential help to CD8 T cells or by their own means has become apparent and suggests the use of CD4 T cells in adoptive T cell therapy. Regarding the development of TCRs for use in CD4 T cells, it is unclear, whether the human CD4 T cell repertoire against shared (self) tumour antigens has been shaped by tolerance mechanisms and lacks highly functional TCRs suitable for therapy. The aim of this study was to generate optimal-affinity major histocompatibility class II (MHC II)-restricted TCRs against the tumour-associated antigen NY-ESO and investigate whether such TCRs can be generated from the human TCR repertoire. TCRs were isolated from CD4 T cells of a human donor representing an antigen-positive host as well as from transgenic mice that express a diverse human TCR repertoire with HLA-DRA/DRB1*0401 restriction and are NY-ESO-negative, thus serving as antigen-negative and therefore non-tolerant source for TCRs. NY-ESO-reactive TCRs from the mice showed superior recognition of tumour cells and higher peptide sensitivity compared to TCRs from humans. We identified a candidate TCR, TCR-3598_2, which, transduced in CD4 T cells, caused tumour regression in combination with NY-ESO-redirected CD8 T cells in a mouse model of adoptive T cell therapy. A clinical version of TCR-3598_2 was tested for functionality in preparation of a clinical trial. These data suggest that MHC II-restricted TCRs against NY-ESO from humanized non-tolerant mice are of optimal affinity unlike human-derived TCRs and that the combined use of MHC I- and II-restricted TCRs against NY-ESO can make adoptive T cell therapy more effective.
