北京大学陈鹏等研究人员合作发现，多模态靶向嵌合体通过利用肿瘤-免疫微环境实现综合免疫疗法。2024年11月5日，《细胞》杂志在线发表了这项成果。
研究人员报告了一种多模态且可编程的平台，能够将多个治疗模块整合到单一的药物中，实现肿瘤靶向同时协同调动肿瘤-免疫微环境（TIME）内的多种免疫细胞。研究人员开发了三重正交连接技术（T-Linker），将不同的治疗小分子和生物分子整合为多模态靶向嵌合体（Multi-TAC）。
EGFR-CD3-PDL1 Multi-TAC在体外、多个人源化小鼠模型以及患者来源的肿瘤模型中表现出优秀的疗效，能够促进T细胞与树突状细胞的共同调动，从而靶向固体肿瘤。此外，Multi-TAC还可构建为协调T细胞与其他免疫细胞类型的工具。Multi-TAC的高度模块化和可编程特性，可能在免疫疗法及其他领域找到广泛应用。
据悉，尽管免疫疗法已彻底改变了癌症治疗，但其疗效受到多种因素的影响，尤其是TIME的复杂性和异质性。能够同时且协同调动TIME中多种免疫细胞的策略仍然非常理想，但也极具挑战性。
附：英文原文
Title: Multimodal targeting chimeras enable integrated immunotherapy leveraging tumor-immune microenvironment
Author: Feng Lin, Shenyi Yin, Zijian Zhang, Ying Yu, Haoming Fang, Zhen Liang, Rujie Zhu, Haitao Zhou, Jianjie Li, Kunxia Cao, Weiming Guo, Shan Qin, Yuxuan Zhang, Chenghao Lu, Han Li, Shibo Liu, Heng Zhang, Buqing Ye, Jian Lin, Yan Li, Xiaozheng Kang, Jianzhong Jeff Xi, Peng R. Chen
Issue&Volume: 2024-11-05
Abstract: Although immunotherapy has revolutionized cancer treatment, its efficacy is affected by multiple factors, particularly those derived from the complexity and heterogeneity of the tumor-immune microenvironment (TIME). Strategies that simultaneously and synergistically engage multiple immune cells in TIME remain highly desirable but challenging. Herein, we report a multimodal and programmable platform that enables the integration of multiple therapeutic modules into single agents for tumor-targeted co-engagement of multiple immune cells within TIME. We developed the triple orthogonal linker (T-Linker) technology to integrate various therapeutic small molecules and biomolecules as multimodal targeting chimeras (Multi-TACs). The EGFR-CD3-PDL1 Multi-TAC facilitated T-dendritic cell co-engagement to target solid tumors with excellent efficacy, as demonstrated in vitro, in several humanized mouse models and in patient-derived tumor models. Furthermore, Multi-TACs were constructed to coordinate T cells with other immune cell types. The highly modular and programmable feature of our Multi-TACs may find broad applications in immunotherapy and beyond.
DOI: 10.1016/j.cell.2024.10.016
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01198-X