肿瘤细胞治疗研究
英文原题：Dual-Target CLDN18.2/HER2 CAR-NK Cells for Advanced Esophageal Adenocarcinoma
这是一项 I/II 期注册临床试验，评估 HER2NK 细胞治疗食管癌的安全性、可行性及初步疗效。当前状态：招募中。计划入组 36 例。试验地点：中国 · 深圳（共 1 个中心，其中中国 1 个）。登记号：NCT07622940。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准： * 组织学确诊为食管腺癌或Siewert I/II型胃食管结合部腺癌（生物学特征符合食管腺癌），疾病不可切除、复发或转移，且不适合根治性治疗； * 晚期疾病至少一线全身治疗后进展，或不能耐受/不适合标准治疗；若当地标准治疗中有生物标志物指导治疗，须已接受该治疗，或有记录表明不适用/不可及； * 按RECIST v1.1至少有一个可测量病灶； * 至少有一种选定靶点阳性：经验证IHC检测CLDN18.2阳性（示例阈值：≥75%肿瘤细胞膜染色中等/强阳性，或达到方案规定的中心实验室阈值），和/或HER2阳性（IHC 3+，或IHC 2+且ISH扩增）； * ECOG体能状态0–1； * 按方案实验室阈值骨髓、肾、肝、肺和心脏功能充分； * 预期寿命≥12周； * 既往治疗的有临床意义毒性已恢复至≤1级（脱发或稳定的内分泌疾病除外）； * 愿意提供存档肿瘤组织；如安全可行，愿意接受新鲜活检； * 有生育能力者妊娠试验阴性，并同意按方案避孕。 排除标准： * 食管鳞癌或其他非腺癌组织学类型； * 已知活动性CNS转移或软脑膜病；既往治疗且稳定的CNS疾病仅在无症状且未使用递增剂量类固醇时可能允许； * 12周内接受基因修饰细胞治疗，或接受可能混淆安全性/疗效结果的其他试验性治疗； * 活动性未控制感染，包括未控制乙肝、丙肝、HIV病毒血症、脓毒症或有临床意义的机会性感染； * 正在接受超过生理性类固醇替代剂量的全身免疫抑制治疗； * 过去2年内有需全身治疗的活动性自身免疫病； * 有临床意义的间质性肺病/肺炎、未控制心血管疾病或LVEF<50%； * 活动性胃肠穿孔、未控制出血或有临床意义的黏膜溃疡，增加研究治疗风险； * 既往实体器官移植或活动性移植物抗宿主病； * 妊娠或哺乳； * 合并需全身治疗的其他活动性恶性肿瘤，方案允许的低风险癌症除外。
Inclusion Criteria: * Histologically confirmed esophageal adenocarcinoma or Siewert I/II gastroesophageal junction adenocarcinoma judged biologically consistent with esophageal adenocarcinoma, unresectable/recurrent/metastatic, and not amenable to curative therapy. * Disease progressed after at least 1 prior systemic regimen for advanced disease, or the participant is intolerant of / ineligible for standard therapy. Biomarker-directed therapy must have been received or deemed inappropriate/unavailable where standard in the local setting. * At least 1 measurable lesion by RECIST v1.1. * Evidence of at least one selected target: CLDN18.2-positive by validated IHC (example threshold: membranous staining in ≥75% of tumor cells with moderate/strong intensity or protocol-specified central threshold), and/or HER2-positive by IHC 3+ or IHC 2+/ISH-amplified disease. * ECOG performance status 0-1. * Adequate marrow, renal, hepatic, pulmonary, and cardiac function per protocol laboratory thresholds. * Life expectancy ≥12 weeks. * Resolution of clinically significant prior-therapy toxicities to grade ≤1 (except alopecia or stable endocrinopathies). * Willingness to provide archival tumor tissue and to undergo fresh biopsy when safely feasible. * Negative pregnancy test for participants of childbearing potential and agreement to protocol-defined contraception. Exclusion Criteria: * Esophageal squamous cell carcinoma or non-adenocarcinoma histology. * Known active CNS metastases or leptomeningeal disease; previously treated stable CNS disease may be allowed only if asymptomatic and off escalating steroids per protocol. * Prior gene-modified cellular therapy within 12 weeks, or another investigational therapy likely to confound interpretation of safety or efficacy. * Active uncontrolled infection, including uncontrolled hepatitis B, hepatitis C, HIV viremia, sepsis, or clinically significant opportunistic infection. * Ongoing systemic immunosuppressive therapy above physiologic steroid replacement. * Active autoimmune disease requiring systemic treatment within 2 years. * Clinically significant interstitial lung disease/pneumonitis, uncontrolled cardiovascular disease, or left ventricular ejection fraction \<50%. * Active gastrointestinal perforation, uncontrolled bleeding, or clinically significant mucosal ulceration that would increase study-treatment risk. * Prior solid organ transplant or active graft-versus-host disease. * Pregnant or breastfeeding. * Another active malignancy requiring systemic therapy, except protocol-permitted low-risk cancers.
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 · 12 months；Recommended phase 2 dose · 6 months
次要终点：Objective response rate (ORR) by RECIST v1.1；Disease control rate (DCR) by RECIST v1.1；Duration of response
受试者接受氟达拉滨和环磷酰胺淋巴细胞清除化疗，随后于第0天静脉输注异体双靶点CLDN18.2/HER2 CAR-NK细胞。剂量扩展阶段如符合方案安全性标准，可在第21天再次输注。
本示例研究评估EBNK-1822H2的安全性、可行性、细胞动力学和初步抗肿瘤活性。EBNK-1822H2是一种示例性的异体脐带血来源双靶点CAR-NK细胞产品，靶向CLDN18.2和HER2，用于标准治疗后复发/难治或转移性食管腺癌成人患者。研究先进行剂量递增，再按生物标志物分层扩展队列；并前瞻性记录EGFR表达，作为抗原逃逸的探索性生物标志物。
This example study evaluates the safety, feasibility, cellular kinetics, and preliminary anti-tumor activity of EBNK-1822H2, an illustrative allogeneic cord blood-derived dual-target CAR-NK cell product directed against CLDN18.2 and HER2, in adults with relapsed/refractory or metastatic esophageal adenocarcinoma after standard therapy. The study uses dose escalation followed by biomarker-defined expansion and prospectively records EGFR expression as an exploratory biomarker of antigen escape.
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