NKG2D CAR-NK adoptive cellular immunotherapy combined with or without PD-1 blockade in the treatment of patients with metastatic colorectal cancer: an exploratory study
Danyang Wang, Бин Ли, Guojie Shen, Hangyu Zhang, Yang Gao, Zhimin Du, Xiaomeng Dai, Xuanwen Bao, Xudong Zhu, Zhou Tong, Dongxue Hu, Lulu Liu, Yi Zheng, Peng Zhao, Shu Wang, Weijia Fang
Abstract
BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide, with limited treatment options for patients with metastatic disease. Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells represent a novel immunotherapeutic approach with potential advantages in safety and allogeneic applicability. METHODS: This is a multi-arm phase I clinical trial (NCT05213195) evaluating the safety and feasibility of NKG2D-based CAR-NK cells expressing membrane-bound IL-15 (mbIL-15) in advanced CRC. Here, we report the results from the cohort expansion stage of this trial. Totally, six heavily pretreated patients were enrolled and received lymphodepletion chemotherapy followed by four infusions of CAR-NK cells in 2 weeks. Two cohorts were designed to assess extended infusion routes and combination with anti-PD-1 antibodies. RESULTS: CAR-NK therapy was well tolerated, with no treatment-related death or serious non-hematologic toxicities. Common adverse events included reversible cytokine-release syndrome (CRS) and mild gastrointestinal symptoms. Notably, potential clinical benefits were observed in patients who received CAR-NK cells in combination with anti-PD-1 therapy, including one patient who achieved stable disease (SD) and two others who experienced prolonged overall survival exceeding 700 days, suggesting a potential synergistic effect. Meanwhile, CAR-NK cells were detectable in peripheral blood within two weeks after infusion. And the combination with PD-1 blockade was associated with substantially increased peak CAR transgene levels compared to monotherapy (median CAR copies, 45,593 versus 1001). CONCLUSION: NKG2D CAR-NK cell therapy, alone or combined with PD-1 blockade, demonstrated a favorable safety profile and potential clinical benefit in advanced CRC, warranting further investigation in larger cohorts.