肿瘤细胞治疗研究
英文原题：Dual-Target GD2/B7-H3 CAR-NK Cells for Pediatric Relapsed or Refractory Neuroblastoma
这是一项 I/II 期注册临床试验，评估细胞治疗用于神经母细胞瘤的安全性、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：NCT07502287。
不限性别 · ≥ 12 Months 且 ≤ 21 Years
纳入标准： • 签署知情同意书／同意参加时年龄12个月～21岁。 • 组织学确诊为神经母细胞瘤或节细胞神经母细胞瘤；存在复发、难治、进展或持续性高危疾病，且无可用的根治性标准治疗方案。 • 根据修订版国际神经母细胞瘤疗效评估标准（rINRC）存在可测量或可评估疾病，包括MIBG显像阳性病灶、CT/MRI可评估软组织病灶和／或骨髓病灶。 • 有可用于中心检测GD2和B7-H3表达的肿瘤材料；至少一种靶点阳性。GD2为核心靶点，B7-H3为补充靶点，用于相关性分析和靶点优先级评估。 • 既往接受过标准神经母细胞瘤治疗，包括抗GD2治疗；如有禁忌、无法获得或因有记录的医学原因拒绝，则除外。 • Lansky或Karnofsky体能状态评分≥50分。 • 预期生存期≥8周。 • 既往治疗导致的有临床意义急性毒性已恢复，并满足方案规定的化疗、生物制剂、放疗及既往细胞治疗洗脱期。 • 器官功能充足：血液学、肾、肝、心、肺功能符合方案规定的实验室和临床阈值。 • 有生育能力者妊娠试验阴性，并同意在方案规定期限内采取有效避孕措施。 • 父母／法定监护人签署书面知情同意书；适当时受试者本人亦须表示同意参加。 排除标准： • 存在未控制的活动性感染，包括菌血症、未控制的病毒感染或侵袭性真菌病。 • 妊娠或哺乳期。 • 存在活动性≥2级移植物抗宿主病，或既往异基因移植后在方案规定洗脱期内为治疗／预防GVHD接受全身免疫抑制治疗。 • 存在有症状或不稳定的中枢神经系统疾病，需要紧急医疗干预。 • 方案规定洗脱期内接受过基因修饰细胞治疗，或既往细胞治疗导致的有临床意义毒性尚未消退。 • 患有需要全身免疫抑制治疗的活动性自身免疫性疾病。 • 存在未控制且有临床意义的心血管、肺、肝、肾或神经系统疾病，可能增加研究风险。 • 已知对氟达拉滨、环磷酰胺、研究产品成分或方案要求的支持治疗药物过敏。 • 已知HIV感染未控制，或乙肝／丙肝未控制。 • 研究者判断会使参加研究不安全或妨碍遵守方案的任何医学、心理社会或后勤状况。
Inclusion Criteria: * Age 12 months to 21 years at consent/assent. * Histologically confirmed neuroblastoma or ganglioneuroblastoma with relapsed, refractory, progressive, or persistent high-risk disease for which no curative standard option is available. * Measurable or evaluable disease according to revised International Neuroblastoma Response Criteria (rINRC), including MIBG-avid disease, CT/MRI-evaluable soft-tissue disease, and/or bone marrow disease. * Tumor material available for central assessment of GD2 and B7-H3 expression; at least one target must be positive. GD2 is treated as the core target and B7-H3 as the complementary target for correlative target-prioritization analyses. * Prior exposure to standard neuroblastoma therapy, including anti-GD2-based therapy, unless contraindicated, unavailable, or declined for a documented medical reason. * Lansky or Karnofsky performance score \>= 50. * Life expectancy \>= 8 weeks. * Recovery from clinically significant acute toxicities of prior therapy and protocol-defined washout from chemotherapy, biologics, radiation, and prior cell therapy. * Adequate organ function: hematologic, renal, hepatic, cardiac, and pulmonary function considered sufficient by protocoldefined laboratory and clinical thresholds. * Negative pregnancy test for patients of childbearing potential and agreement to use effective contraception during the protocol-defined period. * Written informed consent from parent/legal guardian and assent from the participant when appropriate. Exclusion Criteria: * Active uncontrolled infection, including bacteremia, uncontrolled viral infection, or invasive fungal disease. * Pregnancy or breastfeeding. * Active grade \>= 2 graft-versus-host disease, or systemic immunosuppression for treatment/prevention of graft-versushost disease within the protocol-defined washout period after prior allogeneic transplant. * Symptomatic or unstable central nervous system disease requiring urgent medical intervention. * Prior genetically modified cellular therapy within the protocol-defined washout window, or unresolved clinically significant toxicity from prior cell therapy. * Active autoimmune disease requiring systemic immunosuppressive therapy. * Clinically significant uncontrolled cardiovascular, pulmonary, hepatic, renal, or neurologic disorder that would increase study risk. * Known hypersensitivity to fludarabine, cyclophosphamide, study-product components, or supportive-care medications required by the protocol. * Known uncontrolled HIV infection or uncontrolled hepatitis B or C. * Any medical, psychosocial, or logistical condition that, in the investigator's judgment, would make study participation unsafe or would impair protocol adherence.
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) after first CARNK infusion, using protocol-defined DLT criteria. · 28 days；Incidence and severity of treatment-emergent adverse events · Incidence and severity of treatment-emergent adverse events, including CRS and ICANS, graded using CTCAE v5.0 and ASTCT consensus criteria. · 12 months
次要终点：Objective response rate by revised International Neuroblastoma Response Criteria (rINRC).；Duration of response among responders；Progression-free survival；Overall survival
参与者接受方案规定的氟达拉滨／环磷酰胺淋巴细胞清除治疗，随后在第0天按分配的剂量水平或RP2D静脉输注异基因双靶点GD2/B7-H3 CAR-NK细胞。满足预设安全性标准且未发生妨碍治疗的毒性或快速进展时，可在第7天和第14天追加给药。
这项探索性Ⅰ／Ⅱ期研究测试异基因双靶点GD2/B7-H3（CD276）CAR-NK细胞用于复发或难治性神经母细胞瘤儿童及青年患者。淋巴细胞清除后，参与者接受CAR-NK细胞静脉输注；A部分确定推荐的Ⅱ期剂量（RP2D），B部分估算初步活性。
This illustrative Phase 1/Phase 2 study tests allogeneic dual-target GD2/B7-H3 (CD276) CAR-NK cells in children and young adults with relapsed or refractory neuroblastoma. After lymphodepletion, participants receive IV CAR-NK cells;Part A defines the RP2D and Part B estimates preliminary activity
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