文章：

活体影像研究癌症进展和转移

Enhancing cellular immunotherapies in cancer by engineering selective therapeutic resistance

原文发布日期：2024-07-24

DOI: 10.1038/s41568-024-00723-5

类型: Review Article

开放获取: 否

英文摘要：

Adoptive cell therapies engineered to express chimeric antigen receptors (CARs) or transgenic T cell receptors (TCRs) to recognize and eliminate cancer cells have emerged as a promising approach for achieving long-term remissions in patients with cancer. To be effective, the engineered cells must persist at therapeutically relevant levels while avoiding off-tumour toxicities, which has been challenging to realize outside of B cell and plasma cell malignancies. This Review discusses concepts to enhance the efficacy, safety and accessibility of cellular immunotherapies by endowing cells with selective resistance to small-molecule drugs or antibody-based therapies to facilitate combination therapies with substances that would otherwise interfere with the functionality of the effector cells. We further explore the utility of engineering healthy haematopoietic stem cells to confer resistance to antigen-directed immunotherapies and small-molecule targeted therapies to expand the therapeutic index of said targeted anticancer agents as well as to facilitate in vivo selection of gene-edited haematopoietic stem cells for non-malignant applications. Lastly, we discuss approaches to evade immune rejection, which may be required in the setting of allogeneic cell therapies. Increasing confidence in the tools and outcomes of genetically modified cell therapy now paves the way for rational combinations that will open new therapeutic horizons.

摘要翻译： 

旨在通过表达嵌合抗原受体（CAR）或转基因T细胞受体（TCR）来识别清除癌细胞的过继性细胞疗法，已成为实现癌症患者长期缓解的一种前景广阔的治疗策略。该疗法要发挥疗效，工程化细胞必须在治疗相关水平上持续存在，同时避免脱瘤毒性——这在B细胞和浆细胞恶性肿瘤以外的领域一直难以实现。本综述探讨通过赋予细胞对小分子药物或抗体疗法的选择性耐药性，来提升细胞免疫疗法效能、安全性与可及性的理念，从而促进与那些可能影响效应细胞功能物质的联合治疗。我们进一步探索改造健康造血干细胞的用途，使其对抗原导向免疫疗法及小分子靶向治疗产生耐药性，以此拓展上述靶向抗癌药物的治疗窗口，并促进基因编辑造血干细胞在非恶性疾病领域的体内筛选。最后，我们讨论了在异体细胞治疗中可能需要的规避免疫排斥策略。当前对基因修饰细胞疗法工具与疗效信心的日益增强，为合理联合治疗方案铺平了道路，这将开启新的治疗视野。

原文链接：

Enhancing cellular immunotherapies in cancer by engineering selective therapeutic resistance