肿瘤细胞治疗研究
英文原题：Dual-Target CSPG4/GD2 CAR-NK Cells for Advanced Melanoma
这是一项 I/II 期注册临床试验，评估异体 NK 细胞治疗黑色素瘤的安全性、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：NCT07627698。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准： * 签署知情同意时年龄18–75岁； * 组织学确诊为不可切除/转移性皮肤黑色素瘤或转移性葡萄膜黑色素瘤； * 标准治疗后疾病进展、不能耐受标准治疗，或无预计可带来有意义获益的标准治疗选择。皮肤黑色素瘤患者既往须接受抗PD-1/L1治疗（可联合或不联合抗CTLA-4，除非有禁忌）；若BRAF V600突变，须既往接受BRAF/MEK抑制剂或记录为不适合此类治疗。葡萄膜黑色素瘤患者若HLA-A*02:01阳性且符合条件，须既往接受tebentafusp；否则需记录该药不可用/不适合，并至少接受过一种全身治疗； * 存档或新鲜肿瘤组织经中心检测证实表达CSPG4和/或GD2（建议阳性阈值：IHC或等效验证检测显示至少25%存活肿瘤细胞阳性）； * 按RECIST v1.1至少有一个可测量病灶； * ECOG体能状态0–1； * 按方案规定骨髓、肾、肝、心和肺功能充分； * 预期寿命至少12周； * 可纳入已治疗且稳定的脑转移患者，条件为神经系统稳定至少4周且无需递增皮质类固醇； * 愿意采用有效避孕措施，并遵守方案要求的访视、采血及所要求的活检。 排除标准： * 活动性有症状的CNS转移、软脑膜疾病或未控制的癫痫； * 既往异体干细胞移植或实体器官移植；12周内接受过基因修饰细胞治疗；或既往抗癌治疗距淋巴细胞清除时间未满足方案洗脱要求； * 需使用泼尼松等效剂量>10 mg/日的全身免疫抑制剂，或存在需要全身治疗的未控制自身免疫/炎症性疾病； * 活动性未控制感染，包括未控制的HIV、HBV或HCV，或计划开始淋巴细胞清除时发热/脓毒症； * 具有临床意义的心血管疾病、未控制心律失常、近期心肌梗死或未控制血栓栓塞性疾病； * 既往治疗导致的≥2级毒性尚未缓解，但稳定的内分泌病、脱发或白癜风除外； * 妊娠或哺乳； * 研究者认为会使淋巴细胞清除或CAR-NK输注不安全的其他情况。
Inclusion Criteria: * Age 18-75 years at consent. * Histologically confirmed unresectable/metastatic cutaneous melanoma or metastatic uveal melanoma. * Disease progression after standard therapy, intolerance to standard therapy, or no remaining standard option expected to provide meaningful benefit. For cutaneous melanoma: prior anti-PD-1/L1 (with or without antiCTLA-4) unless contraindicated; if BRAF V600-mutant, prior BRAF/MEK inhibitor therapy or documented unsuitability. For uveal melanoma: prior tebentafusp if HLA-A\*02:01-positive and eligible, or documented unsuitability/unavailability plus at least one prior systemic therapy. * Tumor demonstrates CSPG4 and/or GD2 expression in archival or fresh tissue by central testing (suggested positivity threshold: at least 25% viable tumor cells by IHC or equivalent validated assay). * At least 1 measurable lesion by RECIST v1.1. * ECOG performance status 0-1. * Adequate bone marrow, renal, hepatic, cardiac, and pulmonary function per protocol. * Life expectancy of at least 12 weeks. * Treated, stable brain metastases are allowed if neurologically stable for at least 4 weeks and not requiring escalating corticosteroids. * Willingness to use effective contraception and comply with protocol-required visits, blood sampling, and requested biopsies. Exclusion Criteria: * Active symptomatic CNS metastases, leptomeningeal disease, or uncontrolled seizure disorder. * Prior allogeneic stem cell transplant or solid organ transplant; prior gene-modified cellular therapy within 12 weeks; or anti-cancer therapy too close to lymphodepletion per protocol washout rules. * Requirement for systemic immunosuppression greater than 10 mg prednisone equivalent/day or uncontrolled autoimmune/inflammatory disease requiring systemic treatment. * Active uncontrolled infection, including uncontrolled HIV, HBV, or HCV, or fever/sepsis at the time lymphodepletion would begin. * Clinically significant cardiovascular disease, uncontrolled arrhythmia, recent myocardial infarction, or uncontrolled thromboembolic disease. * Grade 2 or higher unresolved toxicities from prior therapy, except stable endocrinopathy, alopecia, or vitiligo. * Pregnancy or breastfeeding. * Any condition that, in the investigator's judgment, would make lymphodepletion or CAR-NK infusion unsafe.
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) using CTCAE v5.0 · 28 Days；Recommended Phase 2 Dose (RP2D) · 42 Days
次要终点：Treatment-emergent adverse events ( TEDE )；Objective response rate (ORR) by RECIST v1.1；Disease control rate (DCR) by RECIST v1.1；Duration of response；Progression-free survival (PFS)；Overall survival
靶点阳性的不可切除/转移性皮肤黑色素瘤或转移性葡萄膜黑色素瘤成人患者接受淋巴细胞清除，随后在计划的三个剂量水平之一接受EBDTKN-401；15天内最多输注3次。
靶点阳性的不可切除/转移性皮肤黑色素瘤受试者，按相同淋巴细胞清除方案后接受RP2D。
靶点阳性的转移性葡萄膜黑色素瘤受试者，按相同淋巴细胞清除方案后接受RP2D。
这是一项首次人体、开放标签、多中心Ⅰ/Ⅱ期研究，在不可切除或转移性皮肤黑色素瘤、以及转移性葡萄膜黑色素瘤成人患者中，评估淋巴细胞清除化疗后给予异体双靶点CSPG4/GD2 CAR-NK细胞（EBDTKN-401）的安全性、可行性、Ⅱ期推荐剂量（RP2D）及初步抗肿瘤活性。受试者疾病须在标准治疗后进展。
This is a first-in-human, open-label, multicenter phase 1/2 study evaluating the safety, feasibility, recommended phase 2 dose (RP2D), and preliminary antitumor activity of allogeneic dual-target CSPG4/GD2 CAR-NK cells (EBDTKN-401) after lymphodepleting chemotherapy in adults with unresectable or metastatic cutaneous melanoma or metastatic uveal melanoma whose disease has progressed after standard therapy
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