癌症免疫疗法
T细胞受体
免疫疗法
蛋白质组
T细胞
主要组织相容性复合体
生物
抗原
链霉菌
MHC I级
癌症研究
免疫学
计算生物学
细胞生物学
免疫系统
生物信息学
作者
Maya Haus‐Cohen,Yoram Reiter
标识
DOI:10.3389/fimmu.2024.1486721
摘要
The clinical success of cancer immunotherapy has driven ongoing efforts to identify novel targets that can effectively guide potent effector functions to eliminate malignant cells. Traditionally, immunotherapies have focused on surface antigens; however, these represent only a small fraction of the cancer proteome, limiting their therapeutic potential. In contrast, the majority of proteins within the human proteome are intracellular, yet they are represented on the cell surface as short peptides presented by MHC class I molecules. These peptide-MHC complexes offer a vast and largely untapped resource for cancer immunotherapy targets. The intracellular proteome, including neo-antigens, presents an exciting opportunity for the development of novel cell-based and soluble immunotherapies. Targeting these intracellular-derived peptide-MHC molecules on malignant cell surfaces can be achieved using specific T-cell receptors (TCRs) or TCR-mimicking antibodies, known as TCR-like (TCRL) antibodies. Current therapeutic strategies under investigation include adoptive cell transfer of TCR-engineered or TCRL-T cells and CAR-T cells that target peptide-MHC complexes, as well as soluble TCR- and TCRL-based agents like bispecific T cell engagers. Recent clinical developments in targeting the intracellular proteome using TCRL- and TCR-based molecules have shown promising results, with two therapies recently receiving FDA approval for the treatment of unresectable or metastatic uveal melanoma and synovial sarcoma. This review focuses on the processes for selecting and isolating TCR- and TCRL-based targeting moieties, with an emphasis on pre-clinical and clinical studies that explore the potential of peptide-MHC targeting agents in cancer immunotherapy.
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