肿瘤细胞治疗研究
英文原题：NK Cell Therapy for Malignant Solid Brain Tumors
这是一项分期未标注的注册临床试验，评估自体 NK 细胞治疗脑肿瘤、胶质母细胞瘤、脑转移瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 27 例。试验地点：中国 · 北京、秦皇岛、郑州（共 4 个中心，其中中国 4 个）。登记号：NCT07552233。
不限性别 · ≥ 18 Years 且 ≤ 70 Years
纳入标准： 1. 男性或女性，年龄18–70岁（含）。 2. 至少有一个可评估病灶；既往活检或病理组织学检查证实为恶性中枢神经系统肿瘤，影像学提示综合治疗后仍持续进展或复发。 3. Karnofsky体能状态（KPS）评分≥60%。 4. 预期生存期>4周，且能够接受增强MRI检查。 5. 入组前至少4周已完成放疗或全身治疗（包括替莫唑胺/贝伐珠单抗或其他药物）。既往治疗相关毒性应按不良事件通用术语标准（CTCAE）6.0版降至≤1级，脱发或白斑等毒性除外。 6. 地塞米松剂量≤4 mg/日或等效皮质类固醇剂量，或未使用地塞米松。 7. 器官和骨髓功能充分，定义如下：白细胞计数（WBC）≥3×10⁹/L；中性粒细胞绝对计数（ANC）>1×10⁹/L；血红蛋白（Hb）≥90 g/L；血小板（PLT）≥80×10⁹/L；丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）<本机构正常值上限（ULN）的1.5倍；血清肌酐<本机构ULN的1.5倍；总胆红素<本机构ULN的1.5倍；凝血酶原时间（PT）和部分凝血活酶时间（PTT）≤本机构ULN的1.25倍。 8. 无明显遗传性疾病。 9. 心功能正常，左心室射血分数>55%。 10. 无出血及凝血障碍。 11. NK细胞输注前48小时内血培养无细菌、真菌或病毒阳性结果，且无脑膜炎迹象。 12. 有生育能力的女性须在治疗开始前7天内妊娠检测为阴性；受试者同意在试验期间及最后一次细胞输注后6个月内采取避孕措施（激素或屏障避孕法，或禁欲）。如试验期间怀孕或怀疑怀孕，应立即告知主管医生。 13. 已签署书面知情同意书。 排除标准： 1. 活动性乙型或丙型肝炎病毒感染、HIV感染或其他未经治疗的活动性感染。 2. 妊娠或哺乳期女性。 3. 器官衰竭。 4. 患有需要免疫或激素治疗的慢性疾病。 5. 对免疫治疗或相关细胞过敏。 6. 未控制的并发疾病。 7. 患有可能影响遵守研究要求的精神疾病或社会状况。 8. 有器官移植史或正在等待器官移植。
Inclusion Criteria: 1. Male or female, age 18-70 years old (both ends included) 2. At least one evaluable lesion with previous biopsy or pathohistologic confirmation of malignant central nervous system tumor, with imaging suggestive of continued progression or recurrence after comprehensive treatment 3. Karnofsky Performance Status (KPS) ≥ 60% 4. Life expectancy \> 4 weeks, and must be able to undergo an MRI with contrast 5. Patients who completed radiotherapy or systemic therapies (including temozolomide/bevacizumab or other agents) for at least 4 weeks prior to enrollment. All prior treatment-related toxicities should be defined as ≤ grade 1 (except for toxicities such as alopecia or leukoplakia) according to the Common Terminology Standard for Adverse Events (CTCAE 6.0) 6. Dexamethasone dose ≤ 4 mg/day or equivalent corticosteroid dose, or no dexamethasone administered 7. Must have adequate organ and marrow function as defined below: * White blood cell count (WBC) ≥ 3 x 10\^9/L * Absolute neutrophil count (ANC) \> 1 x 10\^9/L * Hemoglobin (Hb) ≥ 90 g/L * Platelet (PLT) ≥ 80×10\^9/L * Albumin transaminase (ALT) \& albumin transaminase (AST) \< 1.5 × institutional upper limit of normal (ULN) * Serum creatinine (Cr) \< 1.5 x institutional ULN * Total bilirubin \< 1.5 x institutional ULN * PT \& PTT ≤ 1.25 x institutional ULN 8. No obvious hereditary diseases 9. Normal cardiac function with left ventricular ejection fraction \>55% 10. No bleeding and coagulation disorders 11. Absence of positive blood cultures for bacteria, fungus, or virus within 48-hours prior to NK cell infusion and/or there aren't any indications of meningitis 12. Fertile women must have had a pregnancy test with a negative result within 7 days prior to the start of treatment, and subjects are willing to use contraception (hormonal or barrier method of birth control or abstinence) during the clinical trial and for 6 months after the last cell infusion; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately 13. Signed, written informed consent Exclusion Criteria: 1. Active hepatitis B or C virus, HIV infection, or other untreated active infection 2. Pregnant and lactating women 3. Participants with organ failure 4. Participants with a chronic disease requiring immunologic or hormonal therapy 5. Participants with an allergy to immunotherapy and related cells 6. Participants with uncontrolled intercurrent illness 7. Participants with psychiatric illness/social situations that would limit compliance with study requirements 8. Participants with a history of organ transplantation or who are awaiting organ transplantation
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 Adverse Events (AEs) · Defined as the incidence of ≥ Grade 3-4 adverse events related to NK cells according to common terminology criteria for adverse events (CTCAE) v6.0. · 3 months following NK cells administration；Incidence of Dose-Limiting Toxicities (DLTs) · Defined as events attributable to NK cells infusion within 28 days post-infusion. Grade 3 or higher cytokine release syndrome (CRS) lasting more than 2 weeks, according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria; Any NK cells-related AE requiring intubation; Grade 4 non-hematologic toxicities. · 28 days following initial treatment with NK cells
次要终点：Objective Response Rate (ORR)；Duration of response (DOR)
颅内/鞘内注射：每2周一次，每次1×10⁸个NK细胞；静脉输注：每2周一次，每次2×10⁸个NK细胞。
颅内/鞘内注射：每2周一次，每次1×10⁸个NK细胞；静脉输注：每2周一次，每次9×10⁸个NK细胞。
颅内/鞘内注射：每2周一次，每次1×10⁸个NK细胞；静脉输注：每2周一次，每次2.9×10⁹个NK细胞。
这是一项多中心、开放标签的研究者发起试验，旨在评估对标准治疗方案无效的成年恶性实体性脑肿瘤患者，联合采用颅内和静脉给药方式输注体外扩增并活化的自然杀伤（NK）细胞的安全性、耐受性和可行性。主要目标是确定联合NK细胞治疗的最大耐受剂量（MTD）或最大可行剂量（MFD）。次要目标包括初步评估抗肿瘤活性（以无进展生存期（PFS）、总生存期（OS）、按RANO标准评估的客观缓解率（ORR）衡量），并评估NK细胞输注对肿瘤微环境及外周血免疫状态的影响。
This is a multi-center, open-label investigator-initiated trial (IIT) designed to evaluate the safety, tolerability, and feasibility of combined intracranial and intravenous administration of ex vivo expanded and activated natural killer (NK) cells in adult patients with malignant solid brain tumors who have failed standard treatment modalities. The primary objective is to determine the maximum tolerated dose (MTD) or maximum feasible dose (MFD) of the combined NK cell therapy. Secondary objectives include preliminary assessment of anti-tumor activity as measured by progression-free survival (PFS), overall survival (OS), objective response rate (ORR) per RANO criteria, and evaluation of the immunological effects of NK cell infusion in the tumor microenvironment and peripheral blood.
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