肿瘤细胞治疗研究
英文原题：Exploratory Clinical Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of Tumor Neoantigen-pulsed Autologous Dendritic Cell Injection (YS247, Beijing YSCell Biotech Co., Ltd. [Abbreviated as YS])in Patients With Recurrent or Progressive Glioblastoma
这是一项分期未标注的注册临床试验，评估细胞治疗用于胶质母细胞瘤的安全性、可行性及初步疗效。当前状态：尚未开始招募。计划入组 9 例。登记号：NCT07678138。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准：男女不限，年龄18–75岁；组织学确诊WHO IV级胶质母细胞瘤（GBM）；接受标准治疗（手术及Stupp方案）后MRI确认复发/进展，按RANO标准增强MRI至少有1个可测量病灶，最大径≥1.0 cm；Karnofsky评分≥60，预计生存期≥6个月；ECOG 0–2。样本制备期间允许桥接治疗，但首次给药前洗脱期须≥7天或5个半衰期（取较长者）；研究药物开始前放疗须完成≥8周；既往抗肿瘤治疗毒性恢复至CTCAE 5.0≤1级（脱发除外）。器官功能充分：ANC≥1.5×10⁹/L、ALC≥0.8×10⁹/L、血红蛋白≥90 g/L、血小板≥100×10⁹/L；AST/ALT≤2.5×ULN、总胆红素≤2.5×ULN、白蛋白≥3 g/dL、ALP≤2.5×ULN；INR/APTT≤1.5×ULN（治疗性抗凝者除外）；肌酐≤1.5×ULN或Cockcroft-Gault肌酐清除率≥60 mL/min；心电图正常，超声心动图LVEF≥50%；不吸氧静息SpO₂>92%。有足够静脉通路采集外周血单个核细胞（PBMC），且无采集禁忌；通过手术或活检取得足量肿瘤及血液样本以进行NGS。育龄女性血清妊娠试验阴性；有生育能力的参与者及其伴侣同意在筛查、研究期间及末次给药后6个月内有效避孕；遵守研究操作及随访；自愿参加并签署知情同意。 排除标准：任何其他活动性恶性肿瘤；入组前4周内参加其他临床试验；既往基因转移治疗；首次治疗前4周内接受抗肿瘤治疗（允许的桥接治疗除外），或PBMC单采前14天内输血、使用EPO、G-CSF或GM-CSF；首次治疗前4周内接种活病毒/重组疫苗，或预计末次给药后6个月内需接种减毒活疫苗；严重过敏或超敏反应；MRI对比剂禁忌（起搏器、泵、对比剂过敏）；HIV、HBV、HCV或梅毒阳性；原发/继发免疫缺陷或自身免疫病（如SLE、类风湿关节炎、炎症性肠病、自身免疫性甲状腺病、自身免疫性肝炎、多发性硬化、血管炎、肾小球肾炎、银屑病、未控制哮喘）；治疗前1个月内严重感染、未控制感染，或过去一周使用抗生素（预防用药除外）；首次治疗前30天内接受全身免疫抑制治疗（短期用药经申办方批准可允许；允许吸入激素、盐皮质激素及泼尼松等效剂量≤10 mg/日的低剂量激素）；未控制的全身性疾病，包括NYHA III/IV级心衰、不稳定型心绞痛、心肌梗死、肝硬化、肾衰竭、严重肺病、血液/胃肠/器官衰竭、糖尿病或未控制高血压；研究者判断的ICD-11精神或神经系统疾病（癫痫、精神分裂症、痴呆、成瘾等）；临床显著出血或出血倾向、3个月内动脉/静脉血栓栓塞（TIA、卒中、DVT、PE）；不可逆电解质紊乱；单采前抗肿瘤治疗洗脱不足：细胞毒治疗14天、试验治疗28天、免疫调节治疗7天、靶向治疗28天；妊娠或哺乳；以及研究者认为不适合参加的其他情况。
Inclusion Criteria: 1. Age 18-75 years (inclusive), any gender. 2. Histologically confirmed GBM (WHO Grade IV). 3. Recurrence/progression confirmed by MRI after standard therapy (surgery, Stupp protocol); ≥1 measurable lesion (max diameter ≥1.0 cm) on contrast-enhanced MRI per RANO criteria. 4. KPS score ≥60, expected survival ≥6 months. 5. ECOG score 0-2. 6. Bridging therapy allowed during sample preparation; washout ≥7 days or 5 half-lives (whichever longer) before initial treatment. 7. Radiotherapy completed ≥8 weeks before study drug initiation. 8. Toxicity from prior anti-tumor therapy recovered to CTCAE V5.0 Grade 1 or below (except alopecia). 9. Adequate organ function: * ANC ≥1.5×10⁹/L, ALC ≥0.8×10⁹/L, HGB ≥90 g/L, PLT ≥100×10⁹/L * AST/ALT ≤2.5×ULN, TBIL ≤2.5×ULN, ALB ≥3 g/dL, ALP ≤2.5×ULN * INR/APTT ≤1.5×ULN (except therapeutic anticoagulation) * Cr ≤1.5×ULN or CrCl ≥60 mL/min (Cockcroft-Gault) * Normal ECG, LVEF ≥50% (ECHO) * Resting SpO₂ \>92% without oxygen 10. Adequate venous access for PBMC collection, no contraindications. 11. Sufficient tumor and blood samples for NGS via resection or biopsy. 12. Negative serum pregnancy test (fertile females); effective contraception throughout screening, study, and 6 months after last dose for fertile participants/partners. 13. Compliance with study procedures and follow-up. 14. Voluntary participation and signed informed consent. Exclusion Criteria: 1. Any other active malignancy. 2. Participation in another clinical trial within 4 weeks before enrollment. 3. Prior gene transfer therapy. 4. Concurrent anti-tumor therapy within 4 weeks before initial treatment (except allowed bridging); blood transfusion, EPO, G-CSF, or GM-CSF within 14 days before PBMC apheresis. 5. Live virus/recombinant vaccine within 4 weeks before first treatment; expected need for live attenuated vaccine within 6 months after last dose. 6. Severe allergy or hypersensitivity. 7. MRI contrast contraindications (pacemaker, pump, contrast allergy). 8. Positive HIV, HBV, HCV, or TP. 9. Primary/secondary immunodeficiency or autoimmune disease (SLE, RA, IBD, autoimmune thyroid disease, autoimmune hepatitis, MS, vasculitis, glomerulonephritis, psoriasis, uncontrolled asthma). 10. Severe infection within 1 month before treatment, uncontrolled infection, or antibiotics in the past week (except prophylaxis). 11. Systemic immunosuppressive therapy within 30 days before initial treatment (short-term use allowed with sponsor approval; permitted: inhaled steroids, mineralocorticoids, low-dose steroids ≤10 mg/day prednisone equivalent). 12. Uncontrolled systemic disease (NYHA III/IV heart failure, unstable angina, MI, cirrhosis, renal failure, severe lung disease, hematological/gastrointestinal/organ failure, diabetes, uncontrolled hypertension). 13. ICD-11 psychiatric/neurological disorders (epilepsy, schizophrenia, dementia, addiction) per investigator judgment. 14. Clinically significant bleeding within 3 months or bleeding diathesis; arterial/venous thromboembolism within 6 months (TIA, stroke, DVT, PE). 15. Irreversible electrolyte imbalance. 16. Anti-tumor therapy before apheresis: cytotoxic within 14 days; investigational within 28 days; immunomodulator within 7 days; targeted within 28 days. 17. Pregnant or lactating female. 18. Any other condition deemed unsuitable by the investigator.
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：Safety and Treatment Tolerability · Evaluate the incidence of treatment-related adverse events (TRAEs) of Tumor Neoantigen-pulsed Autologous Dendritic Cell Injection (YS247, Beijing YSCell Biotech Co., Ltd., abbreviated as YS) in patients with recurrent or progressive glioblastoma based on CTCAE v5.0, to assess the safety and tolerability of the product. · From subject enrollment until completion of the 8th treatment cycle (each cycle is 14 days)；Maximum Tolerated Dose (MTD) and Recommended Expanded Dose(RP2D) · Based on the incidence of dose-limiting toxicities (DLTs), establish the MTD of Tumor Neoantigen-pulsed Autologous Dendritic Cell Injection (YS247) for patients with recurrent or progressive glioblastoma, and define the RP2D.
DLT is defined as any study drug-related AE (per CTCAE 5.0) or laboratory abnormality occurring from first dose to 4 weeks post-dose, unrelated to disease progression, comorbidity, or concomitant medication, including:
1. CTCAE Grade 3 non-hematological toxicity lasting \>7 days.
2. Immune-related Grade 3 pneumonia, recurrent Grade 2 pneumonia.
3. Other Grade 3 irAE not recovering to ≤Grade 2 in 3 days or ≤Grade 1 in 14 days with intervention.
4. CTCAE Grade 4 non-hematological toxicity.
5. CTCAE Grade 4 hematological toxicity lasting \>7 days.
6. CTCAE Grade 5 toxicity of any type.
7. Any unexpected toxicity requiring treatment termination per investigator/sponsor judgment. · From subject enrollment until completion of the 8th treatment cycle (each cycle is 14 days)
次要终点：Disease Control Rate (DCR)；Duration of Response (DoR)；the safe and efficacious dose range；Objective Response Rate (ORR)
这是一项单中心、开放标签、剂量递增、多次给药的研究者发起临床试验，评估YS247治疗复发/进展性胶质母细胞瘤的安全性、耐受性、初步疗效及药效学特征。研究分为筛查、基线、治疗和随访阶段。治疗阶段采用“3+3”剂量递增，设低、中、高三个剂量组；YS247每2周皮下注射一次，共连续8次。
这是一项单中心、开放标签、剂量递增、多次给药的研究者发起临床试验，评估肿瘤新抗原致敏自体树突状细胞注射（YS247）治疗复发/进展性胶质母细胞瘤的安全性、耐受性、初步疗效及药效学特征。研究分为筛查、基线、治疗和随访四阶段。治疗阶段采用“3+3”剂量递增，分低、中、高三个剂量组；YS247每2周皮下注射一次，共连续8次。
This is a single-center, open-label, dose-escalation, multiple-dose investigator-initiated trial (IIT). The trial aims to evaluate the safety and tolerability of autologous dendritic cell injection sensitized with tumor neoantigens (YS247) in participants with recurrent or progressive glioblastoma, as well as to assess preliminary efficacy and pharmacodynamic characteristics. The study consists of four phases: screening, baseline, treatment, and follow-up. During the treatment phase, participants will be assigned to three dose groups (low, medium, and high) and enrolled following the "3+3" dose-escalation principle. YS247 will be administered subcutaneously once every 2 weeks for a total of 8 consecutive doses.
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