肿瘤细胞治疗研究
英文原题：EGFR/HER2 Dual-Target CAR-NK Cells for Recurrent or Metastatic HNSCC
这是一项 I/II 期注册临床试验，评估 HER2NK 细胞治疗头颈部鳞癌的安全性、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：NCT07617805。
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口腔、口咽、下咽或喉部鳞状细胞癌，疾病复发或转移，且无法通过根治性手术或放疗治疗。 • 肿瘤符合方案规定的中心检测EGFR和HER2/ERBB2双阳性标准。建议示例阈值：至少50%的存活肿瘤细胞出现EGFR膜染色2+/3+，且至少10%的存活肿瘤细胞HER2 IHC染色2+/3+，和／或符合方案规定的基因扩增／激活性改变。 • 复发／转移性疾病至少接受过1种全身治疗后或治疗期间进展，治疗须包括铂类药物和PD-1/PD-L1抑制剂（有禁忌证或不适合使用者除外）。允许既往使用西妥昔单抗。 • 根据RECIST 1.1至少有1个可测量病灶。 • ECOG体能状态评分0～1分。 • 骨髓、肾、肝、心、肺功能达到方案规定的实验室阈值。 • 预期生存期至少12周。 • 有可用的存档组织，或愿意提供新鲜肿瘤组织进行中心生物标志物检测；愿意接受连续血液采样，如医学上可行，也愿意接受可选的研究活检。 • 有生育能力者妊娠试验阴性，并同意在方案规定的治疗及随访期间采取高效避孕措施。 • 能够理解并签署知情同意书。 排除标准： • 鼻咽癌、唾液腺恶性肿瘤、皮肤鳞状细胞癌、非鳞状组织学类型或原发灶不明癌。 • 存在未经治疗、不稳定或有症状的中枢神经系统转移或软脑膜疾病。 • 方案规定洗脱期内接受过基因修饰过继细胞治疗（如CAR-T、CAR-NK或TCR-T），或既往接受异基因干细胞移植且有活动性移植物抗宿主病。 • 存在未控制的活动性感染，包括未控制的细菌、真菌或病毒感染；病毒载量可检测的活动性乙肝／丙肝；或未控制的HIV感染。 • 患有需要全身免疫抑制治疗的活动性自身免疫性疾病，或淋巴细胞清除前长期使用超过方案阈值的糖皮质激素。 • 存在有临床意义的间质性肺病、依赖氧疗或其他会显著增加细胞治疗风险的严重肺部疾病。 • 存在有临床意义的心血管疾病，包括近期心肌梗死、不稳定型心绞痛、未控制的心律失常、未控制的高血压或症状性心力衰竭。 • 淋巴细胞清除前28天内接受过重大手术，或在方案规定洗脱期内接受过抗癌治疗／试验性治疗。 • 妊娠或哺乳期。 • 已知对氟达拉滨、环磷酰胺或细胞产品辅料严重过敏。 • 研究者认为会损害安全性、方案依从性或知情同意能力的任何医学、精神或社会状况。
Inclusion Criteria: * Age 18 to 75 years at the time of consent. * Histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx that is recurrent or metastatic and not amenable to curative surgery or radiotherapy. * Tumor meets protocol-defined central biomarker criteria for both EGFR and HER2 / ERBB2. Suggested example thresholds: EGFR membranous IHC 2+ / 3+ in at least 50% of viable tumor cells and HER2 IHC 2+ / 3+ in at least 10% of viable tumor cells and / or protocol-defined genomic amplification / activating alteration. * Disease progression on or after at least one prior systemic regimen for recurrent / metastatic disease, including platinum therapy and PD-1 / PD-L1 inhibitor unless contraindicated or not appropriate. Prior cetuximab is allowed. * At least one measurable lesion by RECIST 1.1. * ECOG performance status 0 to 1. * Adequate marrow, renal, hepatic, cardiac, and pulmonary function per protocol-defined laboratory thresholds. * Life expectancy of at least 12 weeks. * Availability of archival tissue or willingness to provide fresh tumor tissue for central biomarker testing; willingness to undergo serial blood sampling and optional research biopsy if medically feasible. * Negative pregnancy test for participants of childbearing potential and agreement to use highly effective contraception during protocol-defined treatment and follow-up windows. * Ability to understand and sign informed consent. Exclusion Criteria: * Nasopharyngeal carcinoma, salivary gland malignancy, cutaneous squamous cell carcinoma, non-squamous histology, or carcinoma of unknown primary. * Untreated, unstable, or symptomatic central nervous system metastases or leptomeningeal disease. * Prior gene-modified adoptive cell therapy (for example CAR-T, CAR-NK, or TCR-T) within a protocol-defined washout period, or prior allogeneic stem-cell transplant with active graft-versus-host disease. * Active uncontrolled infection, including uncontrolled bacterial, fungal, or viral infection; active hepatitis B or C with detectable viral load; or uncontrolled HIV infection. * Active autoimmune disease requiring systemic immunosuppression, or chronic corticosteroid use above the protocoldefined threshold before lymphodepletion. * Clinically significant interstitial lung disease, oxygen dependence, or another serious pulmonary condition that would materially increase cell-therapy risk. * Clinically significant cardiovascular disease including recent myocardial infarction, unstable angina, uncontrolled arrhythmia, uncontrolled hypertension, or symptomatic heart failure. * Major surgery within 28 days before lymphodepletion, or anticancer therapy / investigational therapy within the protocol-defined washout window. * Pregnancy or breastfeeding. * Known severe hypersensitivity to fludarabine, cyclophosphamide, or cell-product excipients. * Any medical, psychiatric, or social condition that, in the investigator's judgment, would compromise safety, protocol compliance, or informed consent.
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；Determination of the recommended Phase 2 dose · By completion of Part A
次要终点：Incidence of treatment-emergent adverse events；Objective response rate (ORR) by RECIST 1.1；Disease control rate (DCR)
参与者在第-5至-3天接受氟达拉滨和环磷酰胺淋巴细胞清除治疗，随后于第0、7和14天输注EGFR/HER2双靶点CAR-NK细胞。部分持续获益且毒性可接受的参与者，在第28天后可考虑接受第二疗程。
本Ⅰ／Ⅱ期示例方案评估异基因EGFR/HER2双靶点CAR-NK细胞用于复发或转移性头颈部鳞状细胞癌（HNSCC）成人患者。肿瘤须符合方案规定的EGFR和HER2/ERBB2共表达标准。研究为生物标志物富集、开放标签、非随机试验，先进行剂量递增安全性导入，随后在推荐的Ⅱ期剂量（RP2D）下开展扩展队列。
This example Phase 1/2 protocol evaluates allogeneic EGFR/HER2 dual-target CAR-NK cells in adults with recurrent or metastatic HNSCC whose tumors meet protocol-defined co-expression criteria for EGFR and HER2/ERBB2. The study is designed as a biomarker-enriched, open-label, non-randomized trial with a dose-escalation safety lead-in followed by an expansion cohort at the recommended Phase 2 dose (RP2D).
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