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

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