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T cell receptor therapeutics: immunological targeting of the intracellular cancer proteome

T细胞受体 抗原 表位 过继性细胞移植 癌症免疫疗法 生物 免疫疗法 人类白细胞抗原 T细胞 癌症研究 癌症 嵌合抗原受体 免疫系统 计算生物学 免疫学 遗传学
作者
Christopher A. Klebanoff,Smita S. Chandran,Brian M. Baker,Sergio A. Quezada,Antoni Ribas
出处
期刊:Nature Reviews Drug Discovery [Nature Portfolio]
卷期号:22 (12): 996-1017 被引量:93
标识
DOI:10.1038/s41573-023-00809-z
摘要

The T cell receptor (TCR) complex is a naturally occurring antigen sensor that detects, amplifies and coordinates cellular immune responses to epitopes derived from cell surface and intracellular proteins. Thus, TCRs enable the targeting of proteins selectively expressed by cancer cells, including neoantigens, cancer germline antigens and viral oncoproteins. As such, TCRs have provided the basis for an emerging class of oncology therapeutics. Herein, we review the current cancer treatment landscape using TCRs and TCR-like molecules. This includes adoptive cell transfer of T cells expressing endogenous or engineered TCRs, TCR bispecific engagers and antibodies specific for human leukocyte antigen (HLA)-bound peptides (TCR mimics). We discuss the unique complexities associated with the clinical development of these therapeutics, such as HLA restriction, TCR retrieval, potency assessment and the potential for cross-reactivity. In addition, we highlight emerging clinical data that establish the antitumour potential of TCR-based therapies, including tumour-infiltrating lymphocytes, for the treatment of diverse human malignancies. Finally, we explore the future of TCR therapeutics, including emerging genome editing methods to safely enhance potency and strategies to streamline patient identification. T cell receptors (TCRs) enable the targeting of proteins selectively expressed by cancer cells, including neoantigens, cancer germline antigens and viral oncoproteins. This Review discusses the current cancer treatment landscape using TCRs and TCR-like molecules, including adoptive cell transfer of T cells expressing endogenous or engineered TCRs or TCR bispecific engagers.
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