Isabella A Revesz, Paul Joyce, Lisa M Ebert, Clive A Prestidge
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引用次数: 0
摘要
γδ T 细胞是 T 淋巴细胞的一个独特亚群,同时具有先天性免疫细胞和适应性免疫细胞的特征,参与癌症免疫监视。γδT细胞是传统T细胞免疫疗法的一个极具吸引力的替代选择,这在很大程度上是因为γδT细胞不受主要组织相容性(MHC)的限制,而且能分泌高水平的细胞因子,具有众所周知的抗肿瘤功能。迄今为止,与体外研究相比,使用γδ T 细胞免疫疗法治疗一系列血液病和实体瘤的临床试验取得的成功有限。γδT细胞疗法无法从临床前试验转化为临床试验的原因是多种因素的综合作用,例如,常用于刺激这些细胞群的γδT细胞激动剂对细胞的吸收有限,但却依赖于细胞内机制;给药的γδT细胞显示出较低的肿瘤浸润水平;以及对γδT细胞抑制受体的认识存在差距。本综述探讨了 γδ T 细胞临床表现与临床前表现之间的差异,并提出了克服这些障碍的可行途径。使用更直接的 γδ T 细胞激动剂、将这些激动剂封装到脂质纳米载体中以改善其药代动力学和药效学特征,以及使用联合疗法来克服检查点抑制和 T 细胞衰竭,都是弥合临床前和临床成功之间差距的方法。考虑到克服这些限制的能力,开发更有针对性的γδ T细胞激动剂-检查点阻断联合疗法有可能在临床试验中取得成功,而迄今为止,这种疗法仍未取得成功。
Effective γδ T-cell clinical therapies: current limitations and future perspectives for cancer immunotherapy
γδ T cells are a unique subset of T lymphocytes, exhibiting features of both innate and adaptive immune cells and are involved with cancer immunosurveillance. They present an attractive alternative to conventional T cell-based immunotherapy due, in large part, to their lack of major histocompatibility (MHC) restriction and ability to secrete high levels of cytokines with well-known anti-tumour functions. To date, clinical trials using γδ T cell-based immunotherapy for a range of haematological and solid cancers have yielded limited success compared with in vitro studies. This inability to translate the efficacy of γδ T-cell therapies from preclinical to clinical trials is attributed to a combination of several factors, e.g. γδ T-cell agonists that are commonly used to stimulate populations of these cells have limited cellular uptake yet rely on intracellular mechanisms; administered γδ T cells display low levels of tumour-infiltration; and there is a gap in the understanding of γδ T-cell inhibitory receptors. This review explores the discrepancy between γδ T-cell clinical and preclinical performance and offers viable avenues to overcome these obstacles. Using more direct γδ T-cell agonists, encapsulating these agonists into lipid nanocarriers to improve their pharmacokinetic and pharmacodynamic profiles and the use of combination therapies to overcome checkpoint inhibition and T-cell exhaustion are ways to bridge the gap between preclinical and clinical success. Given the ability to overcome these limitations, the development of a more targeted γδ T-cell agonist-checkpoint blockade combination therapy has the potential for success in clinical trials which has to date remained elusive.
期刊介绍:
Clinical & Translational Immunology is an open access, fully peer-reviewed journal devoted to publishing cutting-edge advances in biomedical research for scientists and physicians. The Journal covers fields including cancer biology, cardiovascular research, gene therapy, immunology, vaccine development and disease pathogenesis and therapy at the earliest phases of investigation.