Development of T cell receptor‐engineered T cells targeting the sarcoma‐associated antigen papillomavirus binding factor

Abstract

AbstractWe previously identified papillomavirus binding factor (PBF) as an osteosarcoma antigen recognized by an autologous cytotoxic T lymphocyte clone. Vaccination with PBF‐derived peptide presented by HLA‐A24 (PBF peptide) elicited strong immune responses. In the present study, we generated T cell receptor‐engineered T cells (TCR‐T cells) directed against the PBF peptide (PBF TCR‐T cells). PBF TCR was successfully transduced into T cells and detected using HLA‐A*24:02/PBF peptide tetramer. PBF TCR‐T cells generated from a healthy donor were highly expanded and recognized T2‐A24 cells pulsed with PBF peptide, HLA‐A24+ 293T cells transfected with PBF cDNA, and sarcoma cell lines. To establish an adoptive cell therapy model, we modified the PBF TCR by replacing both α and β constant regions with those of mice (hybrid PBF TCR). Hybrid PBF TCR‐T cells also showed reactivity against T2‐A24 cells pulsed with PBF peptide and to HLA‐A24+ 293T cells transfected with various lengths of PBF cDNA including the PBF peptide sequence. Subsequently, we generated target cell lines highly expressing PBF (MFH03‐PBF [short] epitope [+]) containing PBF peptide with in vivo tumorigenicity. Hybrid PBF TCR‐T cells exhibited antitumor effects compared with mock T cells in NSG mice xenografted with MFH03‐PBF (short) epitope (+) cells. CD45+ T cells significantly infiltrated xenografted tumors only in the hybrid PBF TCR T cell group and most of these cells were CD8‐positive. CD8+ T cells also showed Ki‐67 expression and surrounded the CD8‐negative tumor cells expressing Ki‐67. These findings suggest that PBF TCR‐T cell therapy might be a candidate immunotherapy for sarcoma highly expressing PBF.