肿瘤细胞治疗研究
英文原题：Genetically Modified T-cells in Treating Patients With Recurrent or Refractory Malignant Glioma
这是一项 I 期注册临床试验，评估 CAR-T 细胞治疗胶质母细胞瘤、胶质瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 65 例。试验地点：美国 · 杜阿尔特（共 1 个中心）。登记号：NCT02208362。
不限性别 · ≥ 12 Years 且 ≤ 75 Years
纳入标准： 筛查纳入标准： * 既往经组织学确诊为III级或IV级胶质瘤；或既往经组织学确诊为II级胶质瘤，完成标准治疗后现有影像学进展，符合III级或IV级恶性胶质瘤（MG）。 * 初次放疗结束超过12周后，影像学仍显示可测量病灶进展/复发。 * Karnofsky体能状态评分（KPS）≥60%。 * 预期寿命>4周。 * 有生育能力的女性及男性须同意在入组前及研究参与期结束后6个月内采取适当避孕措施（激素或屏障避孕法，或禁欲）；若女性在试验期间妊娠或怀疑妊娠，应立即告知治疗医生。 * 希望之城（COH）临床病理部门通过免疫组化确认肿瘤表达IL13Rα2（≥20%，1+）。 * 所有研究参与者均须能够理解并愿意签署书面知情同意书。 外周血单个核细胞（PBMC）采集资格： * PBMC采集当天，地塞米松用量不得超过2 mg、每日3次。 * 静脉通路适宜。 * 距末次化疗或放疗至少2周。 Rickham储液囊置入资格： * 肌酐<1.6 mg/dL。 * 白细胞（WBC）>2,000/dL，或中性粒细胞绝对计数（ANC）>1,000。 * 血小板≥100,000/dL。 * 国际标准化比值（INR）<1.3。 * 胆红素<1.5 mg/dL。 * ALT和AST<正常值上限的2.5倍。 * 初次放疗完成后至少间隔12周。 * 标准治疗或研究性治疗的洗脱期： * 含亚硝基脲类的化疗方案完成后至少6周。 * 替莫唑胺治疗完成后至少23天；其他不含亚硝基脲类的细胞毒化疗方案完成后至少4周。若患者最近仅接受靶向药物治疗，且相关毒性已恢复，则末次给药至开始研究治疗只需间隔2周；贝伐珠单抗除外，开始研究治疗前须至少洗脱4周。 入组及接受CAR T细胞输注的资格： * 有已放行的冷冻保存T细胞产品。 * 无需补充氧气即可维持血氧饱和度>95%，且胸部X线无进行性影像异常。 * 无需升压药支持，且无有症状的心律失常。 * 无体温>38.5°C；T细胞输注前48小时内无细菌、真菌或病毒血培养阳性，且无脑膜炎征象。 * 血清总胆红素≤正常上限的2倍。 * 转氨酶≤正常上限的2倍。 * 血清肌酐≤1.8 mg/dL。 * 首次T细胞给药前，手术后无未控制的癫痫发作。 * 血小板计数须≥100,000；若为75,000–99,000，可先输注血小板，且输注后计数达到≥100,000，再进行T细胞输注。 * T细胞治疗期间地塞米松用量不得超过2 mg、每日3次。 排除标准： 筛查排除标准： * 需要补充氧气才能维持血氧饱和度>95%，且预计2周内无法缓解。 * 需要升压药支持和/或有症状的心律失常。 * 需要透析。 * 癫痫发作未控制和/或有临床可见的进行性脑病。 * 研究参与者无法理解本方案基本内容和/或参加本I期研究的风险与获益；可由法定监护人代为理解和同意。 * 存在非恶性并发疾病，现有治疗无法良好控制，或严重程度使研究者认为不宜按方案入组。 * 存在任何其他活动性恶性肿瘤。 * 正在接受严重感染治疗或重大手术后恢复中的患者，在研究者确认完全康复前不得入组。 * 存在任何未控制疾病，包括持续或活动性感染；已知活动性乙肝或丙肝；任何活动性感染体征或症状、血培养阳性或影像学感染证据。 * 筛查前4周内确诊HIV感染。
Inclusion Criteria: * SCREENING INCLUSION CRITERIA * Participant has a prior histologically-confirmed diagnosis of a grade III or IV glioma, or has a prior histologically-confirmed diagnosis of a grade II glioma and now has radiographic progression consistent with a grade III or IV malignant glioma (MG) after completing standard therapy * Radiographic evidence of progression/recurrence of the measurable disease more than 12 weeks after the end of the initial radiation therapy * Karnofsky performance status (KPS) \>= 60% * Life expectancy \> 4 weeks * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately * City of Hope (COH) Clinical Pathology confirms IL13R alpha 2+ tumor expression by immunohistochemistry (\>= 20%, 1+) * All research participants must have the ability to understand and the willingness to sign a written informed consent * ELIGIBILITY TO PROCEED WITH PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) COLLECTION * Research participant must not require more than 2 mg three times daily (TID) of dexamethasone on the day of PBMC collection. * Research participant must have appropriate venous access * At least 2 weeks must have elapsed since the research participant received his/her last dose of prior chemotherapy or radiation * ELIGIBILITY TO PROCEED WITH RICKHAM PLACEMENT * Creatinine \< 1.6 mg/dL * White blood cell (WBC) \> 2,000/dl or * Absolute neutrophil count (ANC) \> 1,000 * Platelets \>= 100,000/dl * International normalized ratio (INR) \< 1.3 * Bilirubin \< 1.5 mg/dL * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 2.5 x upper limits of normal * An interval of at least 12 weeks must have elapsed since the completion of initial radiation therapy * Wash-out requirements (standard or investigational): * At least 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen * At least 23 days since the completion of Temodar and/or 4 weeks for any other non-nitrosourea-containing cytotoxic chemotherapy regimen; if a patient's most recent treatment was with a targeted agent only, and s/he has recovered from any toxicity of this targeted agent, then a waiting period of only 2 weeks is needed from the last dose and the start of study treatment, with the exception of bevacizumab where a wash out period of at least 4 weeks is required before starting study treatment * ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH CAR T CELL INFUSION * Research participant has a released cryopreserved T cell product * Research participant does not require supplemental oxygen to keep saturation greater than 95% and/or does not have presence of any radiographic abnormalities on chest x-ray that are progressive * Research participant does not require pressor support and/or does not have symptomatic cardiac arrhythmias * Research participant does not have a fever exceeding 38.5° Celsius (C); there is an absence of positive blood cultures for bacteria, fungus, or virus within 48-hours prior to T cell infusion and/or there aren't any indications of meningitis * Research participant serum total bilirubin does not exceed 2 x normal limit * Research participant transaminases does not exceed 2 x normal limit * Research participant serum creatinine =\< 1.8 mg/dL * Research participant does not have uncontrolled seizure activity following surgery prior to starting the first T cell dose * Research participant platelet count must be \>= 100,000; however, if platelet level is between 75,000-99,000, then T-cell infusion may proceed after platelet transfusion is given and the post transfusion platelet count is \>= 100,000 * Research participants must not require more than 2 mg TID of dexamethasone during T cell therapy Exclusion Criteria: * SCREENING EXCLUSION CRITERIA * Research participant requires supplemental oxygen to keep saturation greater than 95% and the situation is not expected to resolve within 2 weeks * Research participant requires pressor support and/or has symptomatic cardiac arrhythmias * Research participant requires dialysis * Research participant has uncontrolled seizure activity and/or clinically evident progressive encephalopathy * Failure of research participant to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase I study; a legal guardian may substitute for the research participant * Research participants with any non-malignant intercurrent illness which is either poorly controlled with currently available treatment, or which is of such severity that the investigators deem it unwise to enter the research participant on protocol shall be ineligible * Research participants with any other active malignancies * Research participants being treated for severe infection or who are recovering from major surgery are ineligible until recovery is deemed complete by the investigator * Research participants with any uncontrolled illness including ongoing or active infection; research participants with known active hepatitis B or C infection; research participants with any signs or symptoms of active infection, positive blood cultures or radiological evidence of infections * Research participants who have confirmed human immunodeficiency virus (HIV) within 4 weeks of screening
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 Participants With Grade 3 or Higher Toxicity Related to CAR T Cells · Grade 3 or higher toxicity profile for adverse events probably or definitely related to CAR T cells as assessed by the NCI CTCAE version 4.0. · An average of 11 months；Number of Participants Experiencing a Dose Limiting Toxicity (DLT) · Toxicities will be graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. A DLT is defined as events attributable to T-cell infusion (probable or definite) with a few expected events that resolve within a specified time and occurring from the time of initial CAR T cell infusion through 1 week following the last infusion cycle (not including optional cycles) unless otherwise specified in this definition:
1. Two grade 3 toxicities at the same dose with the exception of those grade 3 toxicities listed below.
2. Any grade 3 Cytokine release syndrome (CRS) toxicity lasting more than 72 hours without intervention
3. Any grade 3 or higher allergic reaction
4. Any grade 3 or higher autoimmune reaction
5. Any grade 4 toxicity · Up to 1 week following the last course, up to a total of 4 weeks (not including optional courses 4-6)
次要终点：Number of Participants With Active Response Determined by Response Assessment in Neuro-Oncology (RANO) Criteria；Number of Participants Alive at 6 Months
队列1：Tcm来源的CAR T细胞；瘤内给药，活检后[ICTb]。
队列2：Tcm来源的CAR T细胞；瘤内给药，活检后[ICTb]，或切除后腔内给药[ICTr]。
队列3：Tcm来源的CAR T细胞，脑室内给药[ICV]。
队列4：Tcm来源的CAR T细胞，同时采用ICTb/r和ICV两种给药途径。
队列5：Tn/mem来源的CAR T细胞，同时采用ICTb/r和ICV两种给药途径。
这项I期试验研究基因改造T细胞免疫疗法治疗复发或难治性恶性胶质瘤患者的副作用和最佳剂量。T细胞是一类能够识别并杀伤体内异常细胞的免疫细胞。研究者从患者血液中获取T细胞，在实验室将改造基因导入细胞，这可能帮助T细胞识别并杀伤胶质瘤细胞。基因改造T细胞也可能帮助机体建立针对肿瘤细胞的免疫反应。
This phase I trial studies the side effects and best dose of genetically modified T-cell immunotherapy in treating patients with malignant glioma that has come back (recurrent) or has not responded to therapy (refractory). A T cell is a type of immune cell that can recognize and kill abnormal cells in the body. T cells are taken from the patient's blood and a modified gene is placed into them in the laboratory and this may help them recognize and kill glioma cells. Genetically modified T-cells may also help the body build an immune response against the tumor cells.
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