肿瘤细胞治疗研究
英文原题：Her2 Chimeric Antigen Receptor Expressing T Cells in Advanced Sarcoma
这是一项 I 期注册临床试验，评估自体 T 细胞治疗肉瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 36 例。试验地点：美国 · 休斯顿（共 2 个中心）。登记号：NCT00902044。
不限性别
纳入标准 采集阶段资格： 1. 确诊为难治性HER2阳性肉瘤，或转移性HER2阳性骨肉瘤。 2. Karnofsky／Lansky体能状态评分≥50分。 3. 已向患者／监护人说明知情同意内容，且其理解并签署知情同意书；已向患者／监护人提供知情同意书副本。 治疗阶段资格： 1. 确诊为难治性HER2阳性肉瘤，或既往至少接受过一种全身治疗、治疗后疾病进展的转移性HER2阳性肉瘤。 2. 入组前至少4周已从既往细胞毒性化疗的急性毒性中恢复。如有医学指征，可在治疗期间继续使用PD-1／PD-L1抑制剂。 3. 超声心动图（ECHO）正常（左心室射血分数须在本机构正常范围内）。 4. 预期寿命≥6周。 5. Karnofsky／Lansky体能状态评分≥50分。 6. 胆红素≤正常上限的3倍、AST≤正常上限的3倍、血清肌酐≤正常上限的2倍、血红蛋白≥7.0 g/dL、白细胞>2,000/μL、中性粒细胞绝对计数（ANC）>1,000/μL、血小板>100,000/μL。肌酐>正常上限1.5倍的患者需检测肌酐清除率。 7. 室内空气下脉搏血氧饱和度≥90%。 8. 有性生活的患者须同意在CTL输注后6个月内采取较有效的避孕措施；男性伴侣应使用避孕套。 9. 有可用的自体转导T淋巴细胞，其中HER2 CAR表达率经流式细胞术测定≥15%，且细胞毒性试验中对HER2阳性靶细胞的杀伤率≥20%。 10. 胸部X线检查用于肺部基线评估。 11. 已向患者／监护人说明知情同意内容，且其理解并签署知情同意书；已向患者／监护人提供知情同意书副本。 排除标准 采集阶段： 1. 已知HIV阳性。 2. 既往使用环磷酰胺或氟达拉滨后发生严重毒性。 治疗阶段： 1. 严重并发感染。 2. 已知HIV阳性。 3. 妊娠或哺乳期。 4. 对含鼠源蛋白的产品有超敏反应史。 5. 既往使用环磷酰胺或氟达拉滨后发生严重毒性。
INCLUSION CRITERIA: Procurement Eligibility: 1. Diagnosis of refractory HER2-positive sarcoma or metastatic HER2-positive osteosarcoma. 2. Karnofsky/Lansky score of 50 or greater 3. Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent. Treatment Eligibility: 1. Diagnosis of refractory HER2-positive sarcoma or metastatic HER2-positive sarcoma with disease progression after receiving at least one prior systemic therapy. 2. Recovered from acute toxic effects of all prior cytotoxic chemotherapy at least 4 weeks before entering this study. PD1/PDL1 inhibitors will be allowed to continue during treatment if medically indicated. 3. Normal ECHO (Left ventricular ejection fraction (LVEF) has to be within normal, institutional limits) 4. Life expectancy 6 weeks or greater 5. Karnofsky/Lansky score of 50 or greater 6. Bilirubin 3x or less, AST 3x or less, Serum creatinine 2x upper limit of normal or less, Hgb 7.0 g/dl or greater, WBC greater than 2,000/ul, ANC greater than 1,000/ul, platelets greater than 100,000/ul. Creatinine clearance is needed for patients with creatinine greater than 1.5 times upper limit of normal. 7. Pulse oximetry of 90% or greater on room air 8. Sexually active patients must be willing to utilize one of the more effective birth control methods for 6 months after the CTL infusion. Male partner should use a condom 9. Available autologous transduced T lymphocytes with 15% or more expression of HER2 CAR as determined by flow-cytometry and killing of HER2-positive targets 20 % or greater in cytotoxicity assay. 10. Chest radiograph for baseline evaluation of lungs 11. Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent EXCLUSION CRITERIA: At time of Procurement: 1. Known HIV positivity 2. Severe previous toxicity from cyclophosphamide or fludarabine At time of Treatment: 1. Severe intercurrent infection 2. Known HIV positivity 3. Pregnant or lactating 4. History of hypersensitivity reactions to murine protein-containing products 5. Severe previous toxicity from cyclophosphamide or fludarabine
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 after one injection of HER2-specific T cells · To determine the safety of one intravenous injection of autologous T cells expressing HER2-specific chimeric antigen receptor (CAR) in patients with advanced HER2-positive sarcoma.
To determine the safety of one intravenous injection of 1x10\^8/m\^2 autologous T cells after lymphodepleting chemotherapy. · 6 weeks
次要终点：Frequency of HER2-specific T cells pre and post injection；Change in tumor size from pre to post injection
本组已停止入组。 剂量水平1：1×10⁴个细胞/m² 剂量水平2：3×10⁴个细胞/m² 剂量水平3：1×10⁵个细胞/m²（不使用） 剂量水平4：3×10⁵个细胞/m²（不使用） 剂量水平5：1×10⁶个细胞/m² 剂量水平6：3×10⁶个细胞/m² 剂量水平7：1×10⁷个细胞/m² 剂量水平8：3×10⁷个细胞/m² 剂量水平9：1×10⁸个细胞/m²
自体HER2特异性T细胞联合氟达拉滨。 剂量水平9A：先给予氟达拉滨，随后输注1×10⁸个细胞/m²。
自体HER2特异性T细胞联合氟达拉滨和环磷酰胺。 剂量水平9B：先给予氟达拉滨和环磷酰胺，随后输注1×10⁸个细胞/m²。
剂量水平9C：先给予氟达拉滨和环磷酰胺，随后输注1×10⁸个CAR阳性细胞/m²。
患者患有肉瘤。目前尚无针对其癌症的标准治疗，或现有治疗在部分病例中疗效不足，因此研究者邀请患者参加一项基因转移研究，接受特殊免疫细胞治疗。本研究结合两种抗病方式：抗体和T细胞。抗体是能够保护机体免受病菌或有毒物质侵害的蛋白质；它们通过与这些病菌或物质结合，阻止其生长或发挥毒性。T细胞也称T淋巴细胞，是能够对抗感染的特殊血细胞，可杀伤其他细胞，包括肿瘤细胞或被病菌感染的细胞。抗体和T细胞均曾用于癌症治疗，显示出一定前景，但尚不足以治愈多数患者。既往研究发现，可将新基因导入T细胞，使其识别并杀伤癌细胞。本研究拟进一步将一种新基因导入T细胞，使其识别并杀伤肉瘤细胞。该基因可使T细胞表达一种特异性识别HER2（人表皮生长因子受体2）的抗体，该抗体可与肉瘤细胞结合；此外，该基因还包含CD28，可刺激T细胞并延长其存活。其他T细胞临床研究发现，在输注T细胞前给予化疗，可能延长T细胞在体内存留的时间，从而增强其作用。输注前化疗称为淋巴细胞清除，因为化疗药物经过专门选择，可减少体内淋巴细胞数量。先减少患者自身淋巴细胞，可能有利于输入的T细胞扩增并在体内存留更久，从而更有效地杀伤癌细胞。本研究将使用氟达拉滨，或环磷酰胺联合氟达拉滨进行淋巴细胞清除；这些药物是免疫治疗临床试验中最常用的淋巴清除药物。本研究旨在确定嵌合T细胞的最大安全剂量，并观察该疗法是否可能帮助肉瘤患者；同时评估淋巴清除化疗后给予HER2-CD28 T细胞的安全性。
Patients have a type of cancer called sarcoma. Because there is no standard treatment for the patients cancer at this time or because the currently used treatments do not work fully in all cases, patients are being asked to volunteer to take part in a gene transfer research study using special immune cells. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from diseases caused by germs or toxic substances. They work by binding those germs or substances, which stops them from growing or exerting their toxic effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected with germs. Both antibodies and T cells have been used to treat patients with cancers: they both have shown promise, but have not been strong enough to cure most patients. We have found from previous research that we can put a new gene into T cells that will make them recognize cancer cells and kill them. We now want to see if we can put a new gene in these cells that will let the T cells recognize and kill sarcoma cells. The new gene that we will put in makes an antibody specific for HER2 (Human Epidermal Growth Factor Receptor 2) that binds to sarcoma cells. In addition it contains CD28, which stimulated T cells and make them last longer. 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. Giving chemotherapy before a T cell infusion is called lymphodepletion since the chemotherapy is specifically chosen to decrease the number of lymphocytes in the body. Decreasing the number of patient's lymphocytes first should allow the T cells we infuse to expand and stay longer in your body, and potentially kill cancer cells more effectively. We will use fludarabine or the combination of cyclophosphamide and fludarabine as the chemotherapy agents for lymphodepletion. Cyclophosphamide and fludarabine are the chemotherapy agents most commonly used for lymphodepletion in immunotherapy clinical trials. The purpose of this study is to find the largest safe dose of chimeric T cells, and to see whether this therapy might help patients with sarcoma. Another purpose is to see if it is safe to give HER2-CD28 T cells after lymphodepleting chemotherapy.
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