Ludwig Center and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Nature. 2024 Apr;628(8007):416-423. doi: 10.1038/s41586-024-07233-2. Epub 2024 Mar 27.
Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival 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 immunity, 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 cells. 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.
抗体和嵌合抗原受体 (CAR) T 细胞介导的靶向治疗改善了实体瘤和血液系统恶性肿瘤患者的生存。统称 T 细胞癌症的 T 细胞白血病和淋巴瘤的成年患者生存时间短，缺乏此类靶向治疗。因此，T 细胞癌症特别需要开发 CAR T 细胞和抗体来改善患者的预后。临床前研究表明，靶向 T 细胞受体 β 链恒定区 1 (TRBC1) 可以杀死癌细胞，同时保留足够的健康 T 细胞以维持免疫力，这使得 TRBC1 成为治疗 T 细胞癌症的一个有吸引力的靶点。然而，首例抗 TRBC1 CAR T 细胞的人体临床试验报告称，其反应率低且抗 TRBC1 CAR T 细胞的不明原因丢失。在这里，我们证明 CAR T 细胞因患者正常 T 细胞的杀伤而丢失，从而降低了其疗效。为了解决这个问题，我们开发了一种抗体药物偶联物，它可以在体外杀死 TRBC1 癌细胞，并在小鼠模型中治愈人类 T 细胞癌症。抗 TRBC1 抗体药物偶联物可能为 TRBC1 靶向提供最佳形式，并在 T 细胞癌症患者中产生更好的反应。
