Li Bin, Zhu Xudong, Ge Jingyu, Zhang Hangyu, Gao Yang, Bao Xuanwen, Dai Xiaomeng, Du Zhicheng, Tu Xiaoxuan, Tong Zhou, Fu Qihan, Hu Dongxue, Tian Weihong, Zheng Yi, Liu Lulu, Zhao Peng, Fang Weijia, Wang Shu, Wang Dongrui
Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China; Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou 310000, China.
Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China.
Mol Ther. 2025 Sep 3;33(9):4509-4528. doi: 10.1016/j.ymthe.2025.05.026. Epub 2025 May 27.
Peritoneal metastasis (PM) is a prevalent mode of metastasis in colorectal cancer (CRC) with rapid disease progression and limited treatment options. Locoregional infusion of immune cells have been explored in different types of solid tumors, but the feasibility and safety of locoregional chimeric antigen receptor-natural killer (CAR-NK) cells in treating CRC-PM is still unknown. We report the results of a phase 1 dose-escalation clinical trial (NCT05213195) using intraperitoneal infusion of NKG2D CAR-NK cells in heavily-pretreated patients with CRC-PM, and the immune-modulatory effect of CAR-NK cells was also illustrated using multi-omics analysis and functional validation. Locoregional NKG2D CAR-NK cell therapy showed preliminary efficacy and tolerable toxicity in this study. Of nine patients, three achieved stable disease, and the disease control rate was 33.3%. Notably, CD8 T cells post CAR-NK infusion showed the enrichment of a subset co-expressing CD38 and human leukocyte antigen (HLA)-DR, which were highly clonal and also associated with a cytotoxic phenotype. This activated CD38 HLA-DR T cell subset, together with their effector phenotype and function, was induced and maintained by the secretome of activated CAR-NK cells. Our data provide evidence supporting the feasibility of locoregionally infused CAR-NK cells to treat patients with CRC-PM, and indicate peripheral immune activation after locoregional CAR-NK therapy.
腹膜转移（PM）是结直肠癌（CRC）中一种常见的转移方式，疾病进展迅速且治疗选择有限。在不同类型的实体瘤中已探索了局部区域免疫细胞输注，但局部区域嵌合抗原受体-自然杀伤（CAR-NK）细胞治疗CRC-PM的可行性和安全性仍不清楚。我们报告了一项1期剂量递增临床试验（NCT05213195）的结果，该试验对预处理严重的CRC-PM患者进行腹腔内输注NKG2D CAR-NK细胞，并且还使用多组学分析和功能验证说明了CAR-NK细胞的免疫调节作用。在本研究中，局部区域NKG2D CAR-NK细胞疗法显示出初步疗效和可耐受的毒性。9名患者中，3名病情稳定，疾病控制率为33.3%。值得注意的是，CAR-NK输注后的CD8 T细胞显示共表达CD38和人类白细胞抗原（HLA）-DR的一个亚群富集，这些亚群高度克隆且也与细胞毒性表型相关。这种活化的CD38 HLA-DR T细胞亚群及其效应器表型和功能由活化的CAR-NK细胞的分泌组诱导并维持。我们的数据提供了支持局部区域输注CAR-NK细胞治疗CRC-PM患者可行性的证据，并表明局部区域CAR-NK治疗后外周免疫激活。
