肿瘤细胞治疗研究
英文原题：CAR T Cells to Target GD2 for DMG
这是一项 I 期注册临床试验，评估 GD2CAR-T 细胞治疗胶质瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 12 例。试验地点：欧洲 · 伦敦（共 1 个中心）。登记号：NCT05544526。
不限性别 · ≤ 16 Years
纳入标准： 1. 年龄≥2岁且≤16岁。 2. 组织学确诊为H3K27M突变型弥漫性中线胶质瘤。 3. 影像学可见肿瘤，且病灶局限于脑干或脊髓。 4. 放疗结束后至少间隔6周。 5. 接受其他早期临床试验药物治疗后至少间隔3周或5个半衰期（以较短者为准）。 6. 体能状态：年龄≥10岁者采用Karnofsky评分，年龄<10岁者采用Lansky评分，均须≥40%；DMG所致神经功能缺损稳定者可入组。 7. 中性粒细胞绝对计数≥1.5×10⁹/L，血小板≥100×10⁹/L。 8. 总胆红素<正常值上限（ULN）的1.5倍，ALT<ULN的2.5倍。 9. 血清肌酐<该年龄对应ULN的1.5倍。 10. 青春期后受试者同意接受妊娠检测并在适用时采取适当避孕措施。 11. 已签署书面知情同意书。 排除标准： 1. 输注RQR8/huK28Z CAR-T细胞时正在接受全身性糖皮质激素治疗，地塞米松剂量≥0.05 mg/kg/日或等效剂量。 2. 肿瘤累及丘脑或存在幕上病灶、小脑蚓部或小脑半球病灶（脑桥小脑脚受累允许）。 3. 有临床或影像学证据提示肿瘤确实进展。 4. 存在活动性乙型肝炎、丙型肝炎或HIV感染。 5. 无法耐受白细胞单采。 6. 存在与DMG无关的显著既往神经系统疾病。 7. 存在有临床意义的全身性疾病或医疗状况（如显著心、肺、肝或其他器官功能障碍），研究者判断其可能干扰对试验方案安全性或疗效的评估，或妨碍满足研究要求。 8. 按当地药品说明书（SmPC），存在淋巴细胞清除治疗或使用环磷酰胺／氟达拉滨的任何禁忌证。 9. 存在使用抗凝枸橼酸葡萄糖液的任何禁忌证。 10. 存在置入Ommaya储液囊（或类似导管）的任何禁忌证。 11. 已知对白蛋白、二甲基亚砜（DMSO）或乙二胺四乙酸（EDTA）过敏。 12. 原发性免疫缺陷，或有自身免疫性疾病史（如克罗恩病、类风湿关节炎、系统性红斑狼疮），且过去2年内需要接受全身性免疫抑制治疗／全身性疾病修饰药物治疗。 13. 既往接受过试验性或已获批的基因治疗或细胞治疗产品。 14. 预期寿命<3个月。 15. 输注RQR8/huK28Z CAR-T细胞前3个月内使用过利妥昔单抗（或其生物类似药）。 16. 青春期后受试者处于妊娠期或哺乳期。
Inclusion Criteria: 1. Age ≥ 2 and ≤ 16 years 2. Tissue diagnosis of H3K27M mutant Diffuse Midline Glioma. 3. Radiographically evident tumour restricted to the brain stem or spinal cord. 4. At least 6 weeks following completion of radiation therapy. 5. At least 3 weeks or 5 half-lives, whichever is shorter, after treatment with agents on other early phase clinical trial 6. Performance status: Karnofsky (age ≥ 10 years) or Lansky (age \< 10) score ≥ 40% allowing for stable neurological deficit due to DMG 7. Absolute neutrophil count ≥1.5 x109/L and platelet count ≥ 100 x109/L 8. Total bilirubin \< 1.5 ULN and ALT \< 2.5 ULN 9. Serum creatine \< 1.5 ULN for age. 10. For post-pubertal subjects agreement to have a pregnancy test, use adequate contraception (if applicable) 11. Written informed consent Exclusion Criteria: 1. Systemic corticosteroid therapy ≥ 0.05 mg/kg dexamethasone daily (or equivalent) at time of RQR8/huK28Z CAR T cell infusion 2. Tumour involvement of the thalamus or supratentorial lesions, cerebellar vermis or hemispheres (pontocerebellar peduncle involvement is allowed) 3. Clinical or radiological evidence of true tumour progression 4. Active hepatitis B, C or HIV infection 5. Inability to tolerate leukapheresis 6. Pre-existing significant neurological disorder not related to DMG 7. Clinically significant systemic illness or medical condition (e.g., significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgement of the investigator is likely to interfere with assessment of safety or efficacy of the investigational regimen and its requirements. 8. Any contraindication to lymphodepletion or to the use of Cyclophosphamide or Fludarabine as per the local SmPC 9. Any contraindication to the use of Anticoagulant Citrate Dextrose Solution 10. Any contraindication to Ommaya reservoir insertion (or similar catheter) 11. Known allergy to albumin, DMSO or EDTA 12. Primary immunodeficiency or history of autoimmune disease (e.g., Crohn's, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression /systemic disease modifying agents within the last 2 years 13. Prior treatment with investigational or approved gene therapy or cell therapy products 14. Life expectancy \<3 months 15. Use of rituximab (or rituximab biosimilar) within the last 3 months prior to RQR8/huK28Z CAR T cell infusion 16. Post-pubertal subjects who are pregnant or breastfeeding
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：Toxicity evaluated by the incidence of grade 3-5 toxicity causally related to the ATIMP · Toxicity of GD2 CAR T cells as assessed by the incidence of grade 3-5 toxicity causally related to the ATIMP (particularly severe cytokine release syndrome and severe neurotoxicity). · 28 days；Feasibility of manufacturing GD2 CAR T-cells evaluated by the number of therapeutic products generated · Feasibility of generation of the ATIMP as evaluated by the number of therapeutic products generated and the number of ATIMPs infused (as an intravenous agent (Theme 1) and as an intraventricular agent (Theme 2) after successful manufacture. · 28 days
次要终点：Overall survival (OS)；Progression Free Survival (PFS)；Time to Progression (TTP)；Best objective response rate (ORR)
接受ATIMP治疗，即GD2 CAR-T细胞治疗。
CARMIGO是一项单中心、非随机、开放标签Ⅰ期临床试验，研究一种先进治疗试验用药品（ATIMP），对象为2～16岁的弥漫性中线胶质瘤（DMG）儿童和青年患者。研究将评估ATIMP的制备可行性、GD2 CAR-T细胞治疗的安全性和耐受性，以及给药后GD2 CAR-T细胞在患者体内植入、扩增和持续存在的情况。
The CARMIGO Trial is a single-centre, non-randomised, open label Phase I clinical trial of an Advanced Therapy Investigational Medicinal Product (ATIMP) in children and young adults aged 2-16 years with Diffuse Midline Glioma (DMG). The study will evaluate the feasibility of generating the ATIMP, the safety and tolerability of the GD2CAR T-cell therapy and how effectively GD2CAR T-cells engraft, expand and persist following administration in patients with DMG.
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