肿瘤细胞治疗研究
英文原题：Dual-Target CAR-NK Cells Targeting Mesothelin (MSLN) and MUC1 in Advanced Pancreatic Ductal Adenocarcinoma
这是一项 I/II 期注册临床试验，评估 NK 细胞治疗胰腺癌、急性淋巴细胞白血病的安全性、可行性及初步疗效。当前状态：招募中。计划入组 42 例。试验地点：中国 · 深圳（共 1 个中心，其中中国 1 个）。登记号：NCT07627711。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准： • 签署知情同意书时年龄18～75岁。 • 组织学或细胞学确诊为胰腺导管腺癌（PDAC）。 • 局部晚期不可切除或转移性疾病，且至少接受过1种标准全身治疗后进展，或不耐受／不适合标准治疗。 • 根据RECIST 1.1至少有1个可测量病灶。 • 中心免疫组化（IHC，存档或新鲜活检）显示肿瘤抗原表达：A组须MSLN阳性和／或MUC1阳性；B组须CLDN18.2阳性和／或MUC1阳性。（例如≥50%肿瘤细胞染色强度为2+或3+，或H-score高于方案设定阈值。） • ECOG体能状态评分0～1分。 • 器官功能充足，例如：ANC≥1.0×10⁹/L；血小板≥75×10⁹/L；血红蛋白≥8 g/dL；AST/ALT≤ULN的3倍（肝转移者≤ULN的5倍）；总胆红素≤ULN的1.5倍；肌酐清除率≥50 mL/min。 • 预期生存期≥12周。 • 有生育能力者妊娠试验阴性；同意在研究期间及方案规定的随访期内采取有效避孕措施。 • 能够理解并愿意签署书面知情同意书。 排除标准： • 存在活动性或未治疗的中枢神经系统（CNS）转移或癌性脑膜炎。 • 存在有临床意义且未控制的感染（包括未控制的细菌、真菌或病毒感染）。 • 已知活动性乙肝或丙肝且病毒载量可检测；或已知未控制的HIV感染。 • 既往接受过异基因造血干细胞移植或实体器官移植。 • 过去6个月内接受过基因修饰细胞治疗（如CAR-T／CAR-NK）或既往接受过靶向相同抗原的治疗；正在持续需要全身免疫抑制治疗（如超过生理替代剂量的慢性糖皮质激素）。 • 在方案规定时间内存在有临床意义的心血管疾病（如近期心肌梗死、未控制的心律失常或NYHA Ⅲ／Ⅳ级心力衰竭）。 • 过去2年内患有需要全身治疗的活动性自身免疫性疾病（替代治疗允许）。 • 妊娠或哺乳期。 • 研究者认为会妨碍安全参加研究或结果解释的任何医学、精神或社会状况。
Inclusion Criteria: * Age 18 to 75 years at the time of consent. * Histologically or cytologically confirmed pancreatic ductal adenocarcinoma (PDAC). * Unresectable locally advanced or metastatic disease with progression after at least 1 prior standard systemic therapy regimen, or intolerance/ineligibility for standard therapy. * At least 1 measurable lesion per RECIST v1.1. * Tumor antigen expression by central IHC (archival or fresh biopsy): • Arm A eligibility: MSLN positive and/or MUC1 positive. • Arm B eligibility: CLDN18.2 positive and/or MUC1 positive. (Example threshold: IHC 2+ or 3+ staining in \>=50% of tumor cells, or H-score above protocol-defined cutoff.) * ECOG performance status 0-1. * Adequate organ function (example): ANC \>= 1.0 x 10\^9/L; platelets \>= 75 x 10\^9/L; hemoglobin \>= 8 g/dL; AST/ALT \<= 3x ULN (\<= 5x ULN with liver metastases); total bilirubin \<= 1.5x ULN; creatinine clearance \>= 50 mL/min. * Life expectancy \>= 12 weeks. * Negative pregnancy test for individuals of childbearing potential; agreement to use effective contraception during study participation and for a protocol-defined follow-up period. * Ability to understand and willingness to sign written informed consent. Exclusion Criteria: * Active or untreated CNS metastases or carcinomatous meningitis. * Clinically significant uncontrolled infection (including uncontrolled bacterial, fungal, or viral infection). * Known active hepatitis B or hepatitis C with detectable viral load; known uncontrolled HIV infection. * Prior allogeneic hematopoietic stem cell transplant or solid organ transplant. * Prior gene-modified cellular therapy (e.g., CAR-T/CAR-NK) within 6 months or prior therapy targeting the same antigen(s) Ongoing requirement for systemic immunosuppressive therapy (e.g., chronic corticosteroids above physiologic replacement). * Clinically significant cardiovascular disease (e.g., recent myocardial infarction, uncontrolled arrhythmia, or NYHA class III/IV heart failure) within a protocol-defined period. * Active autoimmune disease requiring systemic treatment in the past 2 years (replacement therapy allowed). * Pregnant or breastfeeding. * Any medical, psychiatric, or social condition that, in the investigator's opinion, would interfere with safe participation 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) · 28 Days；Incidence and severity of treatment-emergent adverse events (TEAEs) · 12 months；Maximum tolerated dose (MTD) · 12 months
次要终点：Objective response rate (ORR) per RECIST v1.1；Disease control rate (DCR)；Duration of response (DOR)
中心IHC证实PDAC肿瘤表达MSLN和／或MUC1的受试者进入A组。
中心IHC证实PDAC肿瘤表达CLDN18.2和／或MUC1的受试者进入B组。
这项研究评估试验性双靶点嵌合抗原受体自然杀伤（CAR-NK）细胞产品用于晚期胰腺导管腺癌（PDAC）患者的安全性、耐受性和初步抗肿瘤活性。根据肿瘤抗原表达，受试者进入以下一种生物标志物队列：（A）间皮素（MSLN）和／或MUC1；（B）Claudin 18.2（CLDN18.2）和／或MUC1。研究采用先剂量递增、后剂量扩展的设计，以确定推荐的Ⅱ期剂量（RP2D），并估算各队列的缓解率。
This example study evaluates the safety, tolerability, and preliminary anti-tumor activity of investigational, dual-targeting chimeric antigen receptor natural killer (CAR-NK) cell products for patients with advanced pancreatic ductal adenocarcinoma (PDAC). Participants are assigned to one of two biomarker-defined cohorts based on tumor antigen expression: (A) Mesothelin (MSLN) and/or MUC1, or (B) Claudin 18.2 (CLDN18.2) and/or MUC1. The study uses a dose-escalation followed by dose-expansion design to define a recommended Phase 2 dose (RP2D) and to estimate response rates in each cohort.
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