Redirection of human T lymphocytes towards HER2 by T cell receptor gene transfer for adoptive T cell transfer (41.6)

Abstract

Abstract The clinical goal of our studies is the adoptive transfer of primary T cells transduced with a HER2-specific T cell receptor (TCR) for patients with HER2-overexpressing breast cancer. HLA-A2-, CD8 T cells were stimulated with allogeneic HLA-A2+ dendritic cells (DC) pulsed with the peptide HER2369-377. HER2369-377-reactive T cells were screened, cloned and further tested in functional assays. The TCR from the HER2-reactive CTL clone KU1 was cloned into a retrovirus. Primary T lymphocytes were transduced with this construct and functionally compared with the parental CTL clone KU1. The TCR-transduced primary T cells recognized the peptide HER2369-377 exogenously loaded onto T2 cells or endogenously expressed by tumor cells and transfectants. Similar to the parental CTL clone KU1, the transgenic T cells were not only able to recognize HER2369-377, but also the corresponding peptides from HER3 and HER4. Following TCR optimization (codon optimization, murinization), the TCR-transduced T cells displayed an enhanced tumor cell recognition. In conclusion, the fine specificity of a HER2-reactive TCR is conserved following transduction into primary T lymphocytes. These results facilitate the design of HER2-directed immunotherapies based on TCR-transduced T cells. The observed cross-recognition especially with HER3 may be beneficial as HER2 and HER3 overexpressing tumors are particularly aggressive. DFG