TRBC1-targeting antibody-drug conjugates for the treatment of T cell cancers

• 成果类型: Article
• 署名作者: Nichakawade, Tushar D.; Ge, Jiaxin; Mog, Brian J.; Lee, Bum Seok; Pearlman, Alexander H.; Hwang, Michael S.; Dinapoli, Sarah R.; Wyhs, Nicolas; Marcou, Nikita; Glavaris, Stephanie; Konig, Maximilian F.; Gabelli, Sandra B.; Watson, Evangeline; Sterling, Cole; Wagner-Johnston, Nina; Rozati, Sima; Swinnen, Lode; Fuchs, Ephraim; Pardoll, Drew M.; Gabrielson, Kathy; Papadopoulos, Nickolas; Bettegowda, Chetan; Kinzler, Kenneth W.; Zhou, Shibin; Sur, Surojit; Vogelstein, Bert; Paul, Suman
• 署名单位: Johns Hopkins University; Johns Hopkins Medicine; Johns Hopkins University; Johns Hopkins Medicine; Howard Hughes Medical Institute; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins Medicine; Johns Hopkins University; Johns Hopkins Medicine; Johns Hopkins University; Johns Hopkins Medicine; Johns Hopkins University; Johns Hopkins Medicine; Johns Hopkins University; Johns Hopkins Medicine; Johns Hopkins University; Roche Holding; Roche Holding USA; Genentech; Merck & Company; Merck & Company USA
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4734
• DOI: 10.1038/s41586-024-07233-2
• 发表日期: 2024-04-11
• 关键词: acute lymphoblastic leukemias; chain constant-region; open-label; activation; complex; potent; immunotherapy; costimulation; expression; lymphoma

摘要

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 beta-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. Anti-TRBC1 antibody-drug conjugates may offer a more potent T cell cancer therapy by bypassing the fratricide that may be limiting the efficacy of anti-TRBC1 CAR T cells in the clinical trial for patients with T cell cancers.