肿瘤细胞治疗研究
英文原题：Dual-Targeting 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：NCT07480928。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准： * 签署知情同意书时年龄18至75岁。 * 经组织学或细胞学确诊的胰腺导管腺癌（PDAC）。 * 不可切除的局部晚期或转移性疾病，在至少1线既往标准全身治疗后进展，或对标准治疗不耐受/不适合。 * 根据RECIST v1.1至少有1个可测量病灶。 * 中心实验室IHC检测（存档或新鲜活检）显示肿瘤抗原表达：• A组入组资格：MSLN阳性和/或MUC1阳性。• B组入组资格：CLDN18.2阳性和/或MUC1阳性。（示例阈值：≥50%肿瘤细胞IHC 2+或3+染色，或H-score高于方案规定的 cutoff 值。） * ECOG体能状态评分0-1。 * 器官功能充分（示例）：ANC ≥ 1.0 x 10^9/L；血小板 ≥ 75 x 10^9/L；血红蛋白 ≥ 8 g/dL；AST/ALT ≤ 3倍ULN（伴肝转移时 ≤ 5倍ULN）；总胆红素 ≤ 1.5倍ULN；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；同意在研究参与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： * 活动性或未经治疗的中枢神经系统转移或癌性脑膜炎。 * 临床显著的不受控制感染（包括未控制的细菌、真菌或病毒感染）。 * 已知活动性乙型肝炎或丙型肝炎且病毒载量可检测；已知未控制的HIV感染 * 既往异基因造血干细胞移植或实体器官移植。 * 6个月内接受过既往基因修饰细胞治疗（如CAR-T/CAR-NK）或既往针对相同抗原的治疗
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)
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)；Progression-free survival (PFS)；Overall survival (OS)
根据中心实验室IHC检测，肿瘤表达MSLN和/或MUC1的PDAC受试者被分配至A组。 干预措施：生物制剂：EB-DNK101双靶向CAR-NK细胞（MSLN + MUC1）；药物： 淋巴细胞清除性化疗（氟达拉滨 + 环磷酰胺）
根据中心实验室IHC检测，肿瘤表达CLDN18.2和/或MUC1的PDAC受试者被分配至B组。
本示例研究评估研究性双靶向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。参与者根据肿瘤抗原表达被分配至两个生物标志物定义的队列之一：（A）间皮素（MSLN）和/或MUC1，或（B）Claudin 18.2（CLDN18.2）和/或MUC1。该研究采用剂量递增后剂量扩展设计，以确定推荐的2期剂量（RP2D）并估计各队列的缓解率。
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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