高亲和力 T 细胞受体 ImmTAC®双特异性分子高效重定向 T 细胞杀伤表达癌-睾丸抗原 PRAME 的肿瘤细胞

PRAME ( Pr eferentially expressed A ntigen in Me lanoma) is a cancer-testis antigen expressed in several tumor indications, representing an attractive anticancer target. However, its intracellular location limits targeting by traditional methods. PRAME peptides are presented on the surface of tumor cells by human leukocyte antigen (HLA) molecules, indicating that a T cell receptor (TCR)-based strategy that redirects T cells to kill PRAME + tumors could be a novel immunotherapeutic option. We confirm that PRAME protein is expressed in cutaneous melanoma, including rare subtypes with limited treatment options, as well as primary and metastatic lung, breast, endometrial, and ovarian tumors. Furthermore, PRAME is expressed homogeneously across tumors with distinct oncogenic mutations, mutation burden, PD-L1 expression, immune infiltration, and features of immune checkpoint resistance. Immunopeptidomic analysis of primary tumors detected HLA class I-restricted PRAME peptides.

A TCR recognizing PRAME peptide SLLQHLIGL was engineered to high affinity and fused to a CD3 engaging domain to create a TCRxCD3 bispecific molecule ( I mmune- m obilizing m onoclonal TCR A gainst C ancer, ImmTAC®) with the ability to redirect polyclonal T cells to efficiently kill PRAME + cells. RS: The degree of T cell activation was positively correlated with peptide-HLA abundance, with as few as 10 epitopes per cell sufficient for target cell killing. Impaired ImmTAC®-redirected cytotoxicity of exhausted T cells was rescued using an anti-PD-1 antibody, supporting the use of a combination strategy to treat tumors with active PDL1-PD1 axes.

Our data demonstrate selective and efficient T cell activation and killing by a PRAME-directed TCRxCD3 bispecific, supporting further investigation in multiple cancer indications.