肿瘤细胞治疗研究
英文原题：Targeting the roots of myeloid malignancies with T cell receptors.
髓系恶性肿瘤是起源于造血干细胞或造血祖细胞的克隆性疾病，对大多数患者而言，异基因造血干细胞移植仍是唯一的治愈性治疗。
髓系恶性肿瘤是源自造血干细胞或造血祖细胞的克隆性疾病；对多数患者而言，异基因造血干细胞移植仍是唯一可能治愈的方法。然而，严重副作用和高复发率凸显了开发新疗法的必要性。靶向 B 细胞特异性表面分子的 CAR-T 在 B 细胞癌中的成功尚未复制到髓系恶性肿瘤。表达癌症靶向 TCR 的工程化 T 细胞可作为替代方法，还能靶向细胞内蛋白质组。本观点文章汇总并回顾了利用 TCR 工程化 T 细胞治疗血液系统恶性肿瘤的临床试验数据，并讨论髓系恶性肿瘤适合 TCR 疗法的特定特征。作者还强调，要实现治愈，需要有效靶向少量且以治疗耐药著称的白血病干细胞，因为它们是髓系恶性肿瘤的根源。这需要鉴定新靶点和新 TCR。文章讨论了可用于此目标的不同靶点类别和策略，并强调标准化临床前测试及公开数据的重要性，以便快速鉴定有前景的 TCR 并推进其临床应用。
Myeloid malignancies are clonal diseases of haematopoietic stem cell or haematopoietic progenitor cell origin, for which allogeneic haematopoietic stem cell transplantation remains the only curative treatment for most patients. However, the severe side effects and high relapse rates underscore the need for novel therapies. The success of adoptive transfer of chimeric antigen receptor (CAR) T cells targeting B cell-specific cell surface molecules in B cell cancers has not been replicated in myeloid malignancies. T cells engineered to express cancer-directed T cell receptors (TCRs) could provide an alternative, enabling targeting also of the intracellular proteome. In this Perspective, we have collated and reviewed available data from clinical trials exploiting TCR-engineered T cells for the treatment of haematological malignancies and discuss specific characteristics that make myeloid malignancies attractive candidates for TCR-based therapies. We also highlight the need to efficiently target the rare and notoriously therapy-resistant leukaemic stem cells, which represent the roots of myeloid malignancies, to achieve cures. This will require identification of novel targets and TCRs, and we discuss different target categories and strategies that can be applied towards this goal. We also highlight the importance of standardized preclinical testing and publicly available data to enable rapid identification and clinical advancement of promising TCRs towards clinical application.
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