肿瘤细胞治疗研究
英文原题：Interleukin-15 Armored Glypican 3-specific Chimeric Antigen Receptor Expressed in T Cells for Pediatric Solid Tumors
这是一项 I 期注册临床试验，评估 T 细胞治疗肝癌、软组织肉瘤、肉瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 14 例。试验地点：美国 · 休斯顿（共 1 个中心）。登记号：NCT04377932。
不限性别 · ≥ 1 Year 且 ≤ 21 Years
采集阶段纳入标准： * 免疫组化证实GPC3阳性实体瘤：阳性肿瘤细胞比例≥25%（范围评分≥2级），染色强度≥2级（0–4分）。 * 年龄≥1岁且≤21岁。 * 预期生存期≥16周。 * Lansky或Karnofsky评分≥60%。 * 肝细胞癌患者可为巴塞罗那临床肝癌分期A、B或C期。 * 肝细胞癌患者Child-Pugh-Turcotte评分<7。 * 知情同意已向患者/监护人解释并由其理解和签署，且已提供副本。 采集阶段排除标准： * 对含鼠源蛋白产品有超敏反应史，或入组前存在人抗鼠抗体（HAMA）；仅适用于既往接受鼠源抗体治疗者。 * 既往器官移植。 * 已知HIV阳性。 * 活动性细菌、真菌或病毒感染，乙肝或丙肝感染除外。 * CNS转移正在进展。 治疗阶段纳入标准： * 年龄≥1岁且≤21岁。 * 肝细胞癌患者可为巴塞罗那临床肝癌分期A、B或C期。 * Lansky或Karnofsky评分≥60%。 * 肝细胞癌患者Child-Pugh-Turcotte评分<7。 * 器官功能充分：Cockcroft–Gault或Schwartz公式估算肌酐清除率≥60 mL/min；血清AST<ULN的5倍；总胆红素<该年龄ULN的3倍；肝细胞癌患者INR≤1.7；ANC>500/μL；血小板>25,000/μL（允许输血，但治疗前须达到该水平）；血红蛋白≥7.0 g/dL（允许输血，但治疗前须达到该水平）；室内空气下脉搏血氧饱和度>90%。 * 一线治疗及至少一个挽救治疗周期后疾病难治或复发。 * 入组前已从所有既往化疗和研究性药物的急性毒性中恢复。 * 有性生活的患者同意从T细胞输注后3个月内采用一种高效避孕方法。 * 知情同意已向患者/监护人解释并由其理解和签署，且已提供副本。 治疗阶段排除标准： * 妊娠或哺乳期。 * 未控制的感染。 * 正在接受全身类固醇治疗（泼尼松等效剂量≥0.5 mg/kg/日）；须在CAR-T细胞输注前至少24小时调整剂量或停药。 * 已知HIV阳性。 * 活动性细菌、真菌或病毒感染，乙肝或丙肝感染除外。 * 既往器官移植。 * 对含鼠源蛋白产品有超敏反应史，或入组前存在HAMA；仅适用于既往接受鼠源抗体治疗者。 * CNS转移正在进展。
Procurement Eligibility Inclusion Criteria: * Diagnosis of GPC3-positive\* solid tumors (as determined by immunohistochemistry with an extent score of \>=Grade 2 \[\>25% positive tumor cells\] and an intensity score of \>= 2 \[scale 0-4\]). * Age ≥ 1 year and ≤ 21 years * Life expectancy of ≥ 16 weeks * Lansky or Karnofsky score ≥60% * Barcelona Clinic Liver Cancer Stage A, B or C (for patients with hepatocellular carcinoma only * Child-Pugh-Turcotte score \<7 (for patients with hepatocellular carcinoma only) * Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent Exclusion Criteria: * History of hypersensitivity reactions to murine protein-containing products OR presence of human anti-mouse antibody (HAMA) prior to enrollment (only patients who have received prior therapy with murine antibodies) * History of organ transplantation * Known HIV positivity * Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections) * Actively progressing CNS metastases Treatment Eligibility Inclusion Criteria: * Age ≥ 1 year and ≤ 21 years * Barcelona Clinic Liver Cancer Stage A, B or C (for patients with hepatocellular carcinoma only) * Lansky or Karnofsky score ≥ 60% * Child-Pugh-Turcotte score \< 7 (for patients with hepatocellular carcinoma only) * Adequate organ function: * Creatinine clearance as estimated by Cockcroft Gault or Schwartz ≥ 60 ml/min * serum AST\< 5 times ULN * total bilirubin \< 3 times ULN for age * INR ≤1.7 (for patients with hepatocellular carcinoma only) * absolute neutrophil count \> 500/microliter * platelet count \> 25,000/microliter (can be transfused but must be at that level prior to treatment) * Hgb ≥7.0 g/dl (can be transfused but must be at that level prior to treatment) * pulse oximetry \>90% on room air * Refractory or relapsed disease after treatment with up- front therapy and at least one salvage treatment cycle * Recovered from acute toxic effects of all prior chemotherapy and investigational agents before entering this study * Sexually active patients must be willing to utilize one of the more effective birth control methods for 3 months after the T-cell infusion. * Informed consent explained to, understood by and signed by patient/ guardian. Patient/guardian given copy of informed consent Exclusion Criteria * Pregnancy or lactation * Uncontrolled infection * Systemic steroid treatment (greater than or equal to 0.5 mg prednisone equivalent/kg/day, dose adjustment or discontinuation of medication must occur at least 24 hours prior to CAR T cell infusion) * Known HIV positivity * Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections) * History of organ transplantation * History of hypersensitivity reactions to murine protein-containing products OR presence of human anti-mouse antibody (HAMA) prior to enrollment (only patients who have received prior therapy with murine antibodies) * Actively progressing CNS metastases
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：Number of Patients With Dose Limiting Toxicity · A dose limiting toxicity is defined as any toxicity that is considered to be primarily related to the GPC3-CAR T cells. Specifically those which are Grade 5; non-hematologic Grade 3-4 not returning to Grade 2 within 72 hours; Grade 2-4 allergic reaction; grade 4 hematologic toxicity that persists for 28 days or greater; all grade 4 CRS and neurologic toxicities and grade 3 CRS and neurologic toxicities that fail to return to Grade 1 within 7 days. · 4 weeks
次要终点：Response Rate；Maximum Tolerated Dose (MTD) of Autologous Glypican-3 Specific Chimeric Antigen Expressing T Cells Co-expressing IL-15 Administered to Patients With GPC3-positive Solid Tumors.
向GPC3阳性实体瘤患者给予GPC3-CAR和IL-15（AGAR）T细胞。
癌症复发、标准治疗后未消退或患者无法接受标准治疗时，可考虑参加本研究。研究使用称为AGAR T细胞的实验性免疫细胞疗法，将抗体识别肿瘤的能力与T细胞杀伤能力结合。研究者将GPC3抗体改造成嵌合抗原受体（GPC3-CAR），使T细胞识别包括儿童肝癌在内的实体瘤表面GPC3蛋白；并加入IL-15基因，帮助CAR-T细胞扩增并在血液中维持更久。实验室研究显示，GPC3-CAR与IL-15联合可增强肿瘤细胞杀伤。研究还将IL-15和可诱导半胱天冬酶9（iCasp9）基因一同导入T细胞；若因副作用需要清除细胞，可给予实验性药物rimiducid激活自杀基因。研究将在GPC3阳性实体瘤患者中测试AGAR T细胞，确定安全的最高剂量、体内持久时间、副作用及初步疗效。AGAR T细胞尚未获FDA批准。
Patients may be considered if the cancer has come back, has not gone away after standard treatment or the patient cannot receive standard treatment. This research study uses special immune system cells called AGAR T cells, a new experimental treatment. The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients. Investigators have found from previous research that they can put a new gene (a tiny part of what makes-up DNA and carries your traits) into T cells that will make them recognize cancer cells and kill them. In the lab, investigators made several genes called a chimeric antigen receptor (CAR), from an antibody called GPC3. The antibody GPC3 recognizes a protein found solid tumors including pediatric liver cancers. This CAR is called GPC3-CAR. To make this CAR more effective, investigators also added a gene that includes IL15. IL15 is a protein that helps CAR T cells grow better and stay in the blood longer so that they may kill tumors better. The mixture of GPC3-CAR and IL15 killed tumor cells better in the laboratory when compared with CAR T cells that did not have IL15 .This study will test T cells that investigators made (called genetic engineering) with GPC3-CAR and the IL15 (AGAR T cells) in patients with GPC3-positive solid tumors such as yours. T cells made to carry a gene called iCasp9 can be killed when they encounter a specific drug called Rimiducid. The investigators will insert the iCasp9 and IL15 together into the T cells using a virus that has been made for this study. The drug (Rimiducid) is an experimental drug that has been tested in humans with no bad side-effects. The investigators will use this drug to kill the T cells if necessary due to side effects. This study will test T cells genetically engineered with a GPC3-CAR and IL15 (AGAR T cells) in patients with GPC3-positive solid tumors. The AGAR T cells are an investigational product not approved by the Food and Drug Administration. The purpose of this study is to find the biggest dose of AGAR T cells that is safe, to see how long they last in the body, to learn what the side effects are and to see if the AGAR T cells will help people with GPC3-positive solid tumors.
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