1区 · 综合性期刊
Article
作者: Paul, Suman ; Pardoll, Drew M ; Konig, Maximilian F ; Gabrielson, Kathy ; Zhou, Shibin ; Hwang, Michael S ; Kinzler, Kenneth W ; Marcou, Nikita ; Gabelli, Sandra B ; Bettegowda, Chetan ; Fuchs, Ephraim ; Lee, Bum Seok ; Ge, Jiaxin ; Sterling, Cole ; Mog, Brian J ; Papadopoulos, Nickolas ; Swinnen, Lode ; Wyhs, Nicolas ; Wagner-Johnston, Nina ; Vogelstein, Bert ; Watson, Evangeline ; Pearlman, Alexander H ; Sur, Surojit ; Glavaris, Stephanie ; Nichakawade, Tushar D ; Rozati, Sima ; DiNapoli, Sarah R
Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies1-9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival10,11 and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor β-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity12, making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells13,14. Here we demonstrate that CAR T cells are lost due to killing by the patient's normal T cells, reducing their efficacy. To circumvent this issue, we developed an antibody-drug conjugate that could kill TRBC1+ cancer cells in vitro and cure human T cell cancers in mouse models. The anti-TRBC1 antibody-drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers.