肿瘤细胞治疗研究
英文原题：Dual-Target CAR-NK Cells for Biomarker-Selected Advanced Colorectal Cancer
这是一项 I/II 期注册临床试验，评估 CAR-NK 细胞治疗结直肠癌的安全性、可行性及初步疗效。当前状态：招募中。计划入组 48 例。试验地点：中国 · 深圳（共 1 个中心，其中中国 1 个）。登记号：NCT07462650。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准： • 组织学确诊不可切除或转移性结直肠腺癌，标准治疗后疾病进展、治疗不耐受或不适合标准治疗。 • 按RECIST v1.1有可测量疾病（未来修订后计划的MRD或切除后队列除外）。 • 肿瘤抗原共表达符合中心实验室对以下任一组合设定的阈值：CEA+GUCY2C、CEA+HER2或GUCY2C+HER2。 • ECOG体能状态评分0至1。 • 器官功能足够，符合方案规定的血液、肾、肝和心脏功能标准。 • 既往治疗相关毒性已恢复至≤1级（稳定的2级神经病变或脱发除外）。 • 预期生存期≥12周。 • 愿意在研究期间及细胞输注后方案规定的时间内采取有效避孕措施。 排除标准： • 活动性未控制感染（包括未控制的HBV/HCV）或已知未控制的HIV感染。 • 有症状或需增加类固醇治疗的活动性中枢神经系统转移（按方案，治疗后稳定的CNS疾病可能允许入组）。 • 过去6个月内接受过基因修饰细胞治疗（CAR-T/CAR-NK/TCR-T），或研究者判断既往治疗会增加严重毒性风险。 • 过去6个月内存在需全身免疫抑制治疗的临床显著自身免疫性疾病。 • DLT观察期内同时接受抗癌治疗（方案允许的桥接治疗除外）。 • 妊娠或哺乳期。 • 有临床意义的心血管疾病（如近期心肌梗死、未控制心律失常）、未控制的肺部疾病或其他会增加风险的严重合并症。 • 已知对研究化疗组分（氟达拉滨/环磷酰胺）或必需支持治疗药物过敏。 • 研究者认为会妨碍参加研究、安全监测或结果解释的任何情况。
Inclusion Criteria: * Histologically confirmed colorectal adenocarcinoma that is unresectable or metastatic and has progressed after, is intolerant to, or is ineligible for standard therapies. * Measurable disease per RECIST v1.1 (unless in minimal residual disease (MRD) or post-resection cohorts if a future amendment is planned). * Tumor antigen co-expression meeting central lab thresholds for one of the following pairs: CEA+GUCY2C, CEA+HER2, or GUCY2C+HER2. * ECOG performance status 0-1. * Adequate organ function (hematologic, renal, hepatic, and cardiac) as defined in protocol. * Recovered to Grade \<=1 from prior therapy-related toxicities (except stable Grade 2 neuropathy or alopecia). * Life expectancy \>= 12 weeks. * Willingness to use effective contraception during study and for a protocol-defined period after cell infusion. Exclusion Criteria: * Active, uncontrolled infection (including uncontrolled HBV/HCV) or known uncontrolled HIV infection. * Active CNS metastases that are symptomatic or require escalating steroids. (Stable treated CNS disease may be allowed per protocol.) * Prior gene-modified cellular therapy (CAR-T/CAR-NK/TCR-T) within 6 months, or any prior therapy that in the investigator's judgment increases risk of severe toxicity. * Clinically significant autoimmune disease requiring systemic immunosuppression within the past 6 months. * Concurrent anti-cancer therapy (other than protocol-permitted bridging) during the DLT window. * Pregnant or breastfeeding. * Significant cardiovascular disease (e.g., recent MI, uncontrolled arrhythmia), uncontrolled pulmonary disease, or other severe comorbidity that would increase risk. * Known hypersensitivity to study chemotherapy components (fludarabine/cyclophosphamide) or required supportive medications. * Any condition that, in the investigator's opinion, would interfere with study participation, safety monitoring, or interpretation of results.
以上为辅助阅读译文。是否适合入组须由主治医生判断，最终以登记平台与研究者确认为准。
主要终点：Incidence of dose-limiting toxicities (DLTs) graded by CTCAE v5.0. · 28 Days；Maximum tolerated dose (MTD) · 28 Days；Objective response rate (ORR) by RECIST v1.1 in the expansion cohort. · 12 weeks
次要终点：Incidence and severity of adverse events (AEs)；Disease control rate (DCR)；Progression-free survival (PFS)
适用于肿瘤同时表达CEA（CEACAM5）和GUCY2C（GCC），且均高于预设阈值的CRC患者。
适用于肿瘤表达CEA和HER2/ERBB2阳性的CRC患者（HER2标准依据CRC检测指南）。
适用于肿瘤表达GUCY2C和HER2/ERBB2阳性的CRC患者（特定亚组）。
本I/II期研究评估异基因双靶点嵌合抗原受体自然杀伤细胞（CAR-NK）产品用于晚期或转移性结直肠癌（CRC）成人患者的安全性、耐受性和初步抗肿瘤活性。根据肿瘤抗原共表达，参与者分入三种双靶点队列之一：（1）CEA+GUCY2C；（2）CEA+HER2；或（3）GUCY2C+HER2。完成剂量递增后，将根据安全性、可行性及早期疗效/生物标志物信号，选择最合适的靶点组合进行剂量扩展。
This Phase 1/2 study evaluates the safety, tolerability, and preliminary anti-tumor activity of an allogeneic dual-target chimeric antigen receptor natural killer (CAR-NK) cell product in adults with advanced or metastatic colorectal cancer (CRC). Participants are assigned to one of three dual-target arms based on tumor antigen co-expression: (1) CEA+GUCY2C, (2) CEA+HER2, or (3) GUCY2C+HER2. Following dose escalation, the most suitable target pair (based on safety, feasibility, and early efficacy/biomarker signals) will be selected for dose expansion.
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