Lo Presti Vania, Buitenwerf Frank, van Til Niek P, Nierkens Stefan
Center for Translational Immunology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
AVROBIO, Cambridge, MA 02139, USA.
Vaccines (Basel). 2020 Dec 3;8(4):733. doi: 10.3390/vaccines8040733.
Recent developments in gene engineering technologies have drastically improved the therapeutic treatment options for cancer patients. The use of effective chimeric antigen receptor T (CAR-T) cells and recombinant T cell receptor engineered T (rTCR-T) cells has entered the clinic for treatment of hematological malignancies with promising results. However, further fine-tuning, to improve functionality and safety, is necessary to apply these strategies for the treatment of solid tumors. The immunosuppressive microenvironment, the surrounding stroma, and the tumor heterogeneity often results in poor T cell reactivity, functionality, and a diminished infiltration rates, hampering the efficacy of the treatment. The focus of this review is on recent advances in rTCR-T cell therapy, to improve both functionality and safety, for potential treatment of solid tumors and provides an overview of ongoing clinical trials. Besides selection of the appropriate tumor associated antigen, efficient delivery of an optimized recombinant TCR transgene into the T cells, in combination with gene editing techniques eliminating the endogenous TCR expression and disrupting specific inhibitory pathways could improve adoptively transferred T cells. Armoring the rTCR-T cells with specific cytokines and/or chemokines and their receptors, or targeting the tumor stroma, can increase the infiltration rate of the immune cells within the solid tumors. On the other hand, clinical "off-tumor/on-target" toxicities are still a major potential risk and can lead to severe adverse events. Incorporation of safety switches in rTCR-T cells can guarantee additional safety. Recent clinical trials provide encouraging data and emphasize the relevance of gene therapy and gene editing tools for potential treatment of solid tumors.
基因工程技术的最新进展极大地改善了癌症患者的治疗选择。有效的嵌合抗原受体T（CAR-T）细胞和重组T细胞受体工程化T（rTCR-T）细胞已进入临床用于治疗血液系统恶性肿瘤，取得了令人鼓舞的结果。然而，为了将这些策略应用于实体瘤的治疗，还需要进一步微调以提高其功能和安全性。免疫抑制微环境、周围基质和肿瘤异质性常常导致T细胞反应性差、功能受损以及浸润率降低，从而阻碍治疗效果。本综述的重点是rTCR-T细胞疗法的最新进展，以提高其功能和安全性，用于实体瘤的潜在治疗，并概述正在进行的临床试验。除了选择合适的肿瘤相关抗原外，将优化的重组TCR转基因有效递送至T细胞，结合基因编辑技术消除内源性TCR表达并破坏特定抑制途径，可以改善过继转移的T细胞。用特定的细胞因子和/或趋化因子及其受体武装rTCR-T细胞，或靶向肿瘤基质，可以提高免疫细胞在实体瘤内的浸润率。另一方面，临床“脱瘤/靶向”毒性仍然是一个主要潜在风险，可能导致严重不良事件。在rTCR-T细胞中加入安全开关可以确保额外的安全性。最近的临床试验提供了令人鼓舞的数据，并强调了基因治疗和基因编辑工具在实体瘤潜在治疗中的相关性。
