研究动态
Articles below are published ahead of final publication in an issue. Please cite articles in the following format: authors, (year), title, journal, DOI.

CAR T 细胞重定向至 B7-H3 用于儿童实体瘤:现状和未来前景。

CAR T cells redirected to B7-H3 for pediatric solid tumors: Current status and future perspectives.

发表日期:2024 Jun
作者: Rebecca Epperly, Stephen Gottschalk, Christopher DeRenzo
来源: Bone & Joint Journal

摘要:

尽管进行了强化治疗,患有复发或难治性实体瘤的儿科患者的预后仍很差,需要新的治疗方法。免疫疗法提供了传统治疗方案的替代方案,但需要鉴定差异表达的抗原,以将抗肿瘤活性导向疾病部位。 B7-H3 (CD276) 是一种免疫调节蛋白,在多种恶性肿瘤中表达,在正常组织中表达有限。 B7-H3 在儿童实体瘤中高表达,包括骨肉瘤、横纹肌肉瘤、尤文肉瘤、肾母细胞瘤、神经母细胞瘤和许多罕见肿瘤。在本文中,我们回顾了针对儿科实体瘤的 B7-H3 靶向嵌合抗原受体 (B7-H3-CAR) T 细胞疗法,报告了临床前开发策略并概述了活跃的儿科临床试验的概况。我们确定了实体瘤 CAR T 细胞治疗成功面临的挑战,包括定位和穿透实体瘤部位、逃避敌对的肿瘤微环境、支持 T 细胞扩增和持久性,以及避免内在的肿瘤耐药性。我们重点介绍克服这些挑战并增强 B7-H3-CAR T 细胞效果的策略,包括先进的 CAR T 细胞设计和联合疗法的结合。
Despite intensive therapies, pediatric patients with relapsed or refractory solid tumors have poor outcomes and need novel treatments. Immune therapies offer an alternative to conventional treatment options but require the identification of differentially expressed antigens to direct antitumor activity to sites of disease. B7-H3 (CD276) is an immune regulatory protein that is expressed in a range of malignancies and has limited expression in normal tissues. B7-H3 is highly expressed in pediatric solid tumors including osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, Wilms tumor, neuroblastoma, and many rare tumors. In this article we review B7-H3-targeted chimeric antigen receptor (B7-H3-CAR) T cell therapies for pediatric solid tumors, reporting preclinical development strategies and outlining the landscape of active pediatric clinical trials. We identify challenges to the success of CAR T cell therapy for solid tumors including localizing to and penetrating solid tumor sites, evading the hostile tumor microenvironment, supporting T cell expansion and persistence, and avoiding intrinsic tumor resistance. We highlight strategies to overcome these challenges and enhance the effect of B7-H3-CAR T cells, including advanced CAR T cell design and incorporation of combination therapies.