肿瘤细胞治疗研究
英文原题：3rd Generation GD-2 Chimeric Antigen Receptor and iCaspase Suicide Safety Switch, Neuroblastoma, GRAIN
这是一项 I 期注册临床试验，评估 GD2T 细胞治疗神经母细胞瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 11 例。试验地点：美国 · 休斯顿（共 2 个中心）。登记号：NCT01822652。
不限性别
采集阶段纳入标准： * 高危神经母细胞瘤持续存在或复发。 * 预期生存期至少12周。 * Karnofsky/Lansky评分≥60%。 * 入组前无HAMA（既往接受鼠源抗体治疗者适用）。 * 已取得父母/监护人和儿童（适用时）的知情同意及赞同。 治疗阶段纳入标准： * 高危神经母细胞瘤持续存在或复发。 * 预期生存期至少12周。 * Karnofsky/Lansky评分≥60%。 * ANC≥500，血小板≥20,000。 * 室内空气下脉搏血氧饱和度≥90%。 * AST和ALT<ULN的5倍。 * 总胆红素<ULN的3倍。 * 血清肌酐<ULN的3倍；肌酐>ULN的1.5倍者须检测肌酐清除率。 * TSH在年龄相应正常范围内。使用甲状腺药物维持甲状腺功能正常者，计划输注前剂量须稳定至少1个月。 * 既往化疗的急性毒性均已恢复。如治疗相关影响已转为慢性（如血小板减少），患者须临床稳定并符合其他全部入组标准。 * 既往接受鼠源抗体治疗者，入组前不得存在人抗鼠抗体（HAMA）。 * 患者有自体转导活化T细胞，且其中GD2表达≥20%。 * 有可供输注的帕博利珠单抗。 * 已取得父母/监护人和儿童（适用时）的知情同意及赞同。 排除标准： 采集阶段：疾病快速进展；对含鼠源蛋白产品有超敏反应史。 治疗阶段：疾病快速进展；正在接受其他研究性药物；对含鼠源蛋白产品有超敏反应史；胸片或CT显示心脏扩大或双侧肺浸润。但影像显示心脏扩大者，如方案治疗开始前3周内超声心动图或MUGA检查显示心功能正常，可入组；双侧肺浸润者，如PET、MIBG功能影像或病理评估不符合活动性神经母细胞瘤，可入组。另排除：肿瘤可能导致气道梗阻；妊娠、哺乳或不愿避孕；正在使用皮质类固醇、他克莫司或环孢素等免疫抑制药；既往接受环磷酰胺或氟达拉滨后发生严重毒性；既往帕博利珠单抗或其他PD-1靶向抗体治疗导致严重毒性。
Inclusion Criteria: PROCUREMENT * High risk neuroblastoma with persistent or relapsed disease * Life expectancy of at least 12 weeks * Karnofsky/Lansky score of 60% or greater * Absence of HAMA prior to enrollment (only in patients that have been previously treated with murine antibodies) * Informed consent and assent (as applicable) obtained from parent/guardian and child TREATMENT: * High risk neuroblastoma with persistent or relapsed disease * Life expectancy of at least 12 weeks * Karnofsky/Lansky score of 60% or greater * Patients must have an ANC greater than or equal to 500, platelet count greater than or equal to 20,000 * Pulse Ox greater than or equal to 90% on room air * AST and ALT less than 5 times the upper limit of normal * Total bilirubin less than 3 times the upper limit of normal * Serum creatinine less than 3 times upper limit of normal. Creatinine clearance is needed for patients with creatinine greater than 1.5 times upper limit of normal * TSH normal for age. Patients using thyroid medication to facilitate a euthyroid state must be on a stable dose for at least 1 month prior to planned infusion * Recovered from acute effects of all prior chemotherapy. If some effects of therapy have become chronic (i.e., treatment associated thrombocytopenia), the patient must be clinically stable and meet all other eligibility criteria * Absence of human anti-mouse antibodies (HAMA) prior to enrollment for patients who have received prior therapy with murine antibodies * Patients must have autologous transduced activated T-cells with greater than or equal to 20% expression of GD2 * Pembrolizumab available for infusion * Informed consent and assent (as applicable) obtained from parent/guardian and child Exclusion Criteria: PROCUREMENT: * Rapidly progressive disease * History of hypersensitivity to murine protein containing products TREATMENT: * Rapidly progressive disease * Currently receiving other investigational drugs * History of hypersensitivity to murine protein containing products * History of cardiomegaly or bilateral pulmonary infiltrates on chest radiograph or CT. However, patients with cardiomegaly on imaging may be enrolled if they have an assessment of cardiac function (i.e., ECHO or MUGA) within 3 weeks of starting protocol therapy that is within normal limits. Additionally, patients with bilateral pulmonary infiltrates on imaging may be enrolled if the lesions are not consistent with active neuroblastoma (i.e., negative on functional imaging with PET or MIBG, or by pathologic assessment). * Evidence of tumor potentially causing airway obstruction * Patients who are pregnant, lactating, or unwilling to use birth control * Patients currently receiving immunosuppressive drugs such as corticosteroids, tacrolimus or cyclosporine * Patients previously experienced severe toxicity from cyclophosphamide or fludarabine * Severe previous toxicity from pembrolizumab or other PD-1 targeted antibody
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 at 6 weeks post T cell infusion · We will measure and assess the adverse events to find the maximum tolerated dose of iC9-GD2 T cells and the safety profile of iC9-GD2 T cells. · 6 weeks after infusion of the last dose of iC9-GD2 T cells to all patients on the study
次要终点：To evaluate the expansion and persistence of 3rd generation iC9-GD2 T cells；Time to progression of disease；Change in serum cytokine and chemokine levels
细胞在5–10分钟内静脉输注；可能追加iC9-GD2 T细胞剂量。
细胞在5–10分钟内静脉输注；可能追加iC9-GD2 T细胞剂量。
新鲜T细胞在5–10分钟内静脉输注；可能追加iC9-GD2 T细胞剂量。
本研究邀请复发或难治性神经母细胞瘤患者参加基因转移研究。研究者已发现，可将嵌合抗原受体（CAR）基因导入T细胞，使其识别并杀伤神经母细胞瘤细胞。既往临床试验使用识别几乎所有神经母细胞瘤细胞表面GD2蛋白的GD2-CAR，输注安全；对输注时仍有疾病的患者，如果血液中GD2 T细胞持续超过6周，疾病进展时间更长。因此，本研究在GD2 T细胞中加入CD28和OX40基因，期望延长细胞存活。本研究旨在确定可安全给予复发/难治性神经母细胞瘤患者的iC9-GD2-CD28-OX40（iC9-GD2）T细胞最高剂量。研究还将在T细胞输注前给予环磷酰胺和氟达拉滨进行淋巴细胞清除，以促进输注细胞扩增和持续存在；并给予帕博利珠单抗，以减轻实体瘤中PD-1相关抑制作用。
Subjects that have relapsed or refractory neuroblastoma are invited to take part in this gene transfer research study. We have found from previous research that we can put a new gene called a chimeric antigen receptor (CAR) into T cells that will make them recognize neuroblastoma cells and kill them. In a previous clinical trial, we used a CAR that recognizes GD2, a protein found on almost all neuroblastoma cells (GD2-CAR). We put this gene into T cells and gave them back to patients that had neuroblastoma. The infusions were safe and in patients with disease at the time of their infusion, the time to progression was longer if we could find GD2 T cells in their blood for more than 6 weeks. Because of this, we think that if T cells are able to last longer, they may have a better chance of killing neuroblastoma tumor cells. Therefore, in this study we will add new genes to the GD2 T cells that can cause the cells to live longer. These new genes are called CD28 and OX40. The purpose of this study will be to determine the highest dose of iC9-GD2-CD28-OX40 (iC9-GD2) T cells that can safely be given to patients with relapsed/refractory neuroblastoma. In other clinical studies using T cells, some investigators found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. This is called lymphodepletion and we think that it will allow the T cells we infuse to expand and stay longer in the body, and potentially kill cancer cells more effectively. The chemotherapy we will use for lymphodepletion is a combination of cyclophosphamide and fludarabine. Additionally, to effectively kill the tumor cells, it is important that the T cells are able to survive and expand in the tumor. Recent studies have shown that solid tumors release a substance (PD1) that can inhibit T cells after they arrive into the tumor tissue. In an attempt to overcome the effect of PD1 in neuroblastoma we will also give a medication called pembrolizumab.
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