肿瘤细胞治疗研究
英文原题：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.
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.
NKG2D CAR-NK 细胞疗法单用或联合 PD-1 阻断，在晚期结直肠癌中显示出良好的安全性特征和潜在临床获益，值得在更大规模队列中进一步研究。
背景：结直肠癌（CRC）仍是全球癌症相关死亡的主要原因之一，转移性疾病患者的治疗选择有限。嵌合抗原受体（CAR）工程化自然杀伤（NK）细胞是一种新型免疫治疗方法，可能具有安全性较好且适用于异体治疗的优势。方法：这是一项多臂I期临床试验（NCT05213195），评估表达膜结合型IL-15（mbIL-15）的NKG2D CAR-NK细胞治疗晚期CRC的安全性和可行性。本文报告该试验队列扩展阶段的结果。共纳入6例既往接受多线治疗的患者，先接受淋巴细胞清除化疗，随后在2周内接受4次CAR-NK细胞输注。研究设置两个队列，用于评估延长输注途径及联合抗PD-1抗体治疗。结果：CAR-NK治疗耐受性良好，未发生治疗相关死亡或严重非血液学毒性。常见不良事件包括可逆性细胞因子释放综合征（CRS）及轻微胃肠道症状。值得注意的是，接受CAR-NK联合抗PD-1治疗的患者出现潜在临床获益，包括1例疾病稳定（SD），另有2例总生存期超过700天，提示可能存在协同作用。输注后两周内可在外周血中检测到CAR-NK细胞。与单药治疗相比，联合PD-1阻断与CAR转基因峰值水平显著升高相关（CAR拷贝数中位数为45,593比1,001）。结论：单独使用或联合PD-1阻断的NKG2D CAR-NK细胞疗法，对晚期CRC显示出良好安全性和潜在临床获益，值得在更大队列中进一步研究。
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.
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