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.

通过表达嵌合抗原受体 (CAR) 或转基因 T 细胞受体 (TCR) 来识别和消除癌细胞的过继细胞疗法已成为实现癌症患者长期缓解的有前景的方法。为了有效，工程细胞必须持续保持在治疗相关水平，同时避免肿瘤外毒性，这在 B 细胞和浆细胞恶性肿瘤之外实现是具有挑战性的。本综述讨论了通过赋予细胞对小分子药物或基于抗体的疗法的选择性抗性来增强细胞免疫疗法的功效、安全性和可及性的概念，以促进与否则会干扰效应细胞功能的物质的联合疗法。我们进一步探索工程健康造血干细胞的效用，以赋予对抗原定向免疫疗法和小分子靶向疗法的抗性，以扩大所述靶向抗癌药物的治疗指数，并促进基因编辑造血干细胞的体内选择用于非恶性应用。最后，我们讨论了逃避免疫排斥的方法，这在同种异体细胞疗法中可能是必需的。人们对转基因细胞疗法的工具和结果的信心不断增强，为合理组合铺平了道路，从而开辟了新的治疗视野。