肿瘤细胞治疗研究
英文原题：Anti-GARP Chimeric Antigen Receptor T Cell Therapy for the Treatment of Recurrent Grade III or IV Gliomas
Anti-GARP Chimeric Antigen Receptor T Cell Therapy for the Treatment of Recurrent Grade III or IV Gliomas
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
这是一项 I 期注册临床试验，评估 CAR-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 30 例。试验地点：美国 · 哥伦布（共 1 个中心）。登记号：NCT06964737。
不限性别 · ≥ 18 Years
纳入标准： • 年龄≥18岁；能够理解并愿意签署书面知情同意书。 • 确诊或临床疑似复发性恶性胶质瘤，包括既往WHO III/IV级高级别胶质瘤，或既往组织学确诊II级胶质瘤且新影像提示高级别胶质瘤。影像和/或组织病理证实复发，或活检证实高危组织学且按神经肿瘤放射学评估（RANO）标准存在可测量病灶。 • 单侧大脑半球单灶、幕上病变。病灶及水肿不得位于脑干、中央前/后回、视觉皮层等重要功能区，也不得位于距运动皮层两脑回以内。 • 如使用地塞米松等激素，治疗时剂量须≤4 mg/日，入组/白细胞单采时不得处于递增剂量；单采和第1次治疗前须有2周洗脱期。 • 未接受且计划不接受贝伐珠单抗。Karnofsky评分≥60。适合接受恶性胶质瘤手术，理想方案为切除>80%–90%肿瘤。 • 白细胞>4,000/μL、血红蛋白>7 g/dL、血小板>100（原登记单位如此）；血清肌酐≤机构ULN的1.5倍；肝功能检查≤机构ULN的1.5倍。 • 有生育能力女性须在研究开始前7天内妊娠试验阴性。所有有生育能力者须使用医生批准的避孕措施，并从前2周起、研究期间及末次T细胞输注后6个月内不捐献精子；女性末次输注后6个月内不得哺乳。 • 静脉通路充分（单采前确认）；预期生存期>12周。研究主要研究者判断患者可能完成试验，并能在干预期保持神经症状稳定。 排除标准： • 除本研究胶质瘤外有其他恶性肿瘤史；以下情况可由研究者酌情允许：筛选前至少2年接受根治性治疗且无复发证据、未接受其他抗癌治疗（激素治疗除外）；转移或死亡风险极低的恶性肿瘤（如充分治疗的宫颈原位癌、非黑色素瘤皮肤癌、局限性前列腺癌、乳腺导管原位癌或I期子宫癌）；无转移且未接受活动性治疗（抗雄激素治疗除外）的前列腺癌。 • 自身免疫病，或需长期大剂量激素（>10 mg/日）/免疫抑制治疗的其他疾病。既往使用激素者须在单采前≥7天停药，或将剂量减至<2 mg/kg/日。 • 入组前14天内同时使用其他研究药物（包括某些支持治疗药物）。接受替莫唑胺等抗癌药者须在白细胞单采前停药14天，并在CAR-T 治疗干预期间持续停药。 • 活动性真菌、细菌、病毒或其他感染且需静脉抗微生物治疗；可用预防性抗微生物药物。活动性侵袭性真菌感染者排除，即使正在接受口服抗真菌药也不例外。 • 对研究产品、稀释剂或乳剂过敏。 • 过去3个月内有未控制癫痫发作史。
Inclusion Criteria: * Patients are ≥ 18 years old * Capacity to understand and willingness to provide written informed consent * Diagnosis or clinical suspicion of recurrent malignant glioma, including: * History of high-grade glioma (World Health Organization \[WHO\] grade III or IV), or * Prior, histologically-confirmed diagnosis of grade II glioma with new radiographic findings consistent with a high-grade glioma * Imaging and/or histopathological confirmation of recurrent disease, or verification of "high risk" histology confirmed by a biopsy with measurable disease by the Radiologic Assessment in Neuro-Oncology (RANO) criteria * Patient has unifocal disease in one hemisphere and is supratentorial. Lesion and edema can not be located in eloquent locations (e.g., brainstem, pre-/post-central gyrus, visual cortex) or within 2 gyri of motor strip. * If on steroids such as dexamethasone, must be on a low dose (≤ 4mg per day) at the time of treatment, and not at an ascending dosage schedule at time of enrollment/leukapheresis * Prior to apheresis and treatment 1 a 2- week washout should be observed * Subjects must not have received bevacizumab therapy and are not planned to start such therapy * Karnofsky performance score (KPS) ≥ 60 * Subject is a surgical candidate for surgery for malignant glioma with the intent of resecting \>80-90% of the tumor as the ideal treatment option * White blood cells (WBC) \> 4,000 cells/uL * Hemoglobin (Hgb) \> 7 gm/dL * Platelets (Plt) \> 100/dL * Serum creatinine ≤ 1.5 x institutional upper limit of normal * Liver function tests within 1.5 x institutional upper limit of normal * Women of reproductive potential must have a negative pregnancy test within 7 days of study start. All patients of reproductive potential must use a physician-approved contraceptive and refrain from sperm donation for at least two weeks prior, during, and six months after final T cell infusion. Women must refrain from breastfeeding for six months after final T cell infusion * Sufficient venous access, to be confirmed prior to apheresis * Life expectancy of greater than 12 weeks * PI clinical judgement of patients who will likely complete the trial and are able to maintain stable neurologic symptoms during intervention period Exclusion Criteria: * Patients who have a history of malignancy other than the glioma under investigation in this study, except patients with the following malignancies/treatment characteristics, who are eligible at the investigator's discretion: * Patients with a history of malignancy that has been treated with curative intent at least 2 years prior to screening and with no evidence of relapse, if no concurrent anti-cancer therapy (except hormonal therapy) is being given * Patients with a history of malignancy with a negligible risk of metastasis or death (e.g., 5-year OS rate \> 90%) such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer * Patients who have prostate cancer with no evidence of metastatic disease and are not on active therapy, except anti-androgen therapy * History of autoimmune disease, or other diseases require long-term administration of high-dose steroids \[\> 10 mgs/day\] or immunosuppressive therapies * Research participants who received steroids must have either received their last dose of steroids 7 days or more prior to apheresis or have dosage tapered to \< 2mg/kg/day * Patients being treated concurrently (within 14 days prior to study enrollment) with any other investigational agent * Examples of other investigational agents that would be exclusionary include supportive care agents * Patients receiving anti-cancer agents such as chemotherapy (e.g., temozolomide) must stop treatment 14 days prior to undergoing apheresis and remain off therapy throughout the duration of CAR T therapeutic intervention * Patients with active fungal, bacterial, viral, or other infection that requires intravenous antimicrobials * Prophylactic antimicrobials are allowed * Patients with active invasive fungal infection should be excluded even if the treatment is oral antimicrobials * History of allergy to study products/diluents/emulsions * Recent history (within last 3 months) of uncontrolled seizures
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：Dose limiting toxicities · The rate, frequency and severity will be defined using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5. Will be summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. · Up to 30 days after the first dose
次要终点：Incidence of adverse events；Cytokine levels and immunophenotype in cerebrospinal fluid (CSF)；Duration of anti-glycoprotein-A repetitions predominant (GARP) chimeric antigen receptor (CAR) T cell persistence and phenotype in CSF；Objective response rate (ORR)；Progression-free survival (PFS)；Overall survival (OS)；Correlation of GARP expression levels with outcomes；Frequency and phenotype of anti-GARP CAR T cells in tumor tissue
第-14天进行白细胞单采；第0天手术并置入脑脊液储液装置。若无疾病进展或不可接受毒性，于第14、21、28、35和42天进行抗GARP CAR-T 瘤腔内输注。筛选时进行超声心动图或MUGA检查；研究期间采集脑脊液和血液样本，并进行腰椎穿刺、胸片及MRI检查。
以上邮箱 / 电话是登记库里的申办方联系方式，通常不直达某家医院。中国中心的联系方式请以医院或登记平台最新公示为准。
本Ⅰ期试验评估抗糖蛋白A重复序列主要蛋白（GARP）嵌合抗原受体（CAR）T细胞治疗复发性WHO III或IV级胶质瘤患者的安全性、副作用、最佳剂量及疗效。CAR-T 治疗是从患者血液中采集T细胞，在实验室中加入可识别肿瘤细胞特定蛋白（本研究为GARP）的CAR基因，扩增后再回输患者。研究将评估该疗法用于复发性高级别胶质瘤的安全性、耐受性和潜在疗效。
This phase I trial tests the safety, side effects, and best dose of anti-glycoprotein-A repetitions predominant (GARP) chimeric antigen receptor (CAR) T cell therapy and how well it works in treating patients with grade III or IV gliomas that have come back after a period of improvement (recurrent). CAR T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack tumor cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein, such as GARP, on the patient's tumor cells is added to the T cells in the laboratory. The special receptor is called a CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain tumors. Giving anti-GARP CAR T cell therapy may be safe, tolerable, and/or effective in treating patients with recurrent grade III or IV gliomas.
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