双 T 细胞受体/嵌合抗原受体工程化 NK-92 细胞靶向 HPV16 E6 癌蛋白和肿瘤相关抗原 L1CAM，对肿瘤细胞表现出增强的细胞毒性和特异性

The human papillomavirus type 16 (HPV16) causes a large fraction of genital and oropharyngeal carcinomas. To maintain the transformed state, the tumor cells must continuously synthesize the E6 and E7 viral oncoproteins, which makes them tumor-specific antigens.

Indeed, specific T cell responses against them have been well documented and CD8 + T cells engineered to express T cell receptors (TCRs) that recognize epitopes of E6 or E7 have been tested in clinical studies with promising results, yet with limited clinical success. Using CD8 + T cells from peripheral blood of healthy donors, we have identified two novel TCRs reactive to an unexplored E6 18-26 epitope. These TCRs showed limited standalone cytotoxicity against E6 18-26 -HLA-A*02:01-presenting tumor cells.

However, a single-signaling domain chimeric antigen receptor (ssdCAR) targeting L1CAM, a cell adhesion protein frequently overexpressed in HPV16-induced cancer, prompted a synergistic effect that significantly enhanced the cytotoxic capacity of NK-92/CD3/CD8 cells armored with both TCR and ssdCAR when both receptors simultaneously engaged their respective targets, as shown by live microscopy of 2-D and 3-D co-cultures.

Thus, virus-specific TCRs from the CD8 + T cell repertoire of healthy donors can be combined with a suitable ssdCAR to enhance the cytotoxic capacity of the effector cells and, indirectly, their specificity.