Abstract:

In recent years, immunotherapy has been a breakthrough for clinical treatment of major diseases, such as cancers, whose efficacy and safety in treatment of solid tumors, however, requires further improvements. Meanwhile, the concept and technologies of synthetic biology have also gained substantial development, along with studies on basic immunology and practices in the immunotherapy, giving birth to a new discipline, 'synthetic immunology'. Synthetic immunology aims to engineer biological devices or equipments to reshape, renormalize and rebuild the immune system for rational manipulation of immune responses in immunotherapy against major diseases. This review focuses on the development of immunotherapy driven by synthetic immunology. For future synthetic immune cell therapy, the chassis cell is the key element. Among effector immune cells, Natural Killer (NK) cells are cytotoxic innate lymphocytes that recognize and kill tumor cells without the need for priming. NK-based cell therapy, with proven tolerability and efficacy against tumors, is known for its low toxicity and suitable for allogenic use. These unique features of NK cells make them a potentially ideal chassis for future 'universal' synthetic immune cell therapy, whose anti-tumor efficacy could be further strengthened by arming of NK-adapted chimeric antigen receptors for precise recognition of tumors and of gene circuits for intelligent responses against tumors. In addition, technologies such as large-scale expansion and closed, automatic, and programmable 'cell factory' will lay the essential basis for 'off-the-shelf' supply of these synthetic immune cells. Besides synthetic immune cell therapy, synthetic immune molecules represent another arm of future synthetic immunology-driven immunotherapy. High-throughput technologies, multi-omics, and humanized mouse models will aid the rational design of these synthetic molecules towards reduced toxicity and enhanced efficacy, thus providing more possibilities for manipulation of immune responses. In the future, synthetic immune molecules will cooperate with synthetic immune cell therapy to further improve the efficacy and safety of anti-tumor immune therapy.

Key words: chimeric antigen receptor, 'off-the-shelf ' supply, cell factory, gene editing, checkpoint immune therapy

摘要：

近年来，免疫治疗在肿瘤等重大疾病治疗领域取得了突破性的进展，然而当前免疫治疗在应对实体瘤等方面的有效性和安全性仍有待提高。另一方面，合成生物学的理念和技术也取得了长足的发展，其与免疫学基础研究及免疫治疗实践相融合，诞生了“合成免疫学”新学科，后者将驱动免疫治疗的进一步发展。本文概述了肿瘤免疫治疗的现状及合成免疫学诞生的背景，对天然杀伤细胞（NK细胞）在肿瘤免疫中的作用及NK细胞疗法进行了介绍，并详细综述了设计构建合成免疫细胞和合成免疫分子的相关进展。研究表明，NK细胞由于其独特的属性，可能是“通用型”合成免疫细胞疗法的理想底盘细胞，通过精准识别肿瘤的嵌合抗原受体及智能响应性基因回路等的装载，将实现NK细胞的功能增效，并在NK细胞大规模扩增技术及封闭式、自动化、可编程“细胞工厂”等的支撑下，实现合成免疫细胞的“货架式”供应模式。除了合成免疫细胞疗法之外，减毒增效的合成免疫分子则为人工操控免疫应答提供了更多的可能性。展望未来，合成免疫学驱动的免疫细胞疗法将与新型的合成免疫分子相辅相成，进一步提高抗肿瘤免疫疗法的有效性和安全性。

关键词: 嵌合抗原受体, 货架式供应, 细胞工厂, 基因编辑, 检查点疗法