肿瘤细胞治疗研究
英文原题：EGFR806 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults
EGFR806 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults
这是一项 I 期注册临床试验，评估 CD19 细胞治疗用于实体瘤、骨肉瘤、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 44 例。试验地点：美国 · 西雅图（共 1 个中心）。登记号：NCT03618381。
不限性别 · ≥ 1 Year 且 ≤ 30 Years
纳入标准： * A组和B组最初各2名入组并接受治疗的受试者：年龄≥15岁且≤30岁；之后入组者：年龄≥1岁且≤30岁； * 组织学确诊为表达EGFR的恶性非CNS实体瘤； * 疾病难治或复发； * 能耐受单采，或已有可用于制备的单采产品； * 预期寿命≥8周； * Lansky或Karnofsky评分≥50； * 已从既往化疗、免疫治疗及放疗的显著急性毒性中恢复； * 若无现成单采产品或T细胞产品：末次化疗/生物治疗后≥7天；末次抗肿瘤抗体治疗（包括免疫检查点抑制剂）后≥3个半衰期或30天（取较短者）；骨髓清除治疗及异体/自体干细胞移植后≥6周；末次全身性皮质类固醇治疗后≥7天（允许生理性替代剂量）；神经母细胞瘤患者距末次I-131 MIBG治疗≥12周； * 若既往基因修饰细胞治疗在入组时已检测不到，则允许； * 接受非清髓性治疗后自体干细胞输注者，满足其他条件即可入组； * 器官功能及实验室指标充分； * 有生育能力者同意采取高效避孕措施。 排除标准： * 除原发恶性实体瘤外存在其他活动性恶性肿瘤； * 当前存在相关CNS病理状况； * 活动性GVHD，或入组前4周内为治疗/预防GVHD接受免疫抑制治疗； * 活动性严重感染； * 原发性免疫缺陷综合征； * 入组时正接受外照射放疗； * 正在接受任何抗癌药物或化疗； * 妊娠或哺乳； * 不愿意同意/许可参加研究及15年随访； * 研究者认为会使患者不能接受本方案治疗的任何情况。
Inclusion Criteria: * First 2 subjects enrolled and treated in both Arm A and Arm B: age ≥ 15 and ≤ 30 years * Subsequent subjects: age ≥ 1 and ≤30years * Histologically diagnosed malignant, non-CNS solid tumor expressing EGFR * Evidence of refractory or recurrent disease * Able to tolerate apheresis or has apheresis product available for use in manufacturing * Life expectancy ≥ 8 weeks * Lansky or Karnofsky score ≥ 50 * Recovered from significant acute toxic effects of all prior chemotherapy, immunotherapy, and radiotherapy * If no apheresis product or T cell product is available,≥ 7 days post last chemotherapy/biologic therapy administration * If no apheresis product or T cell product is available,≥ 3 half lives or 30 days, whichever is shorter, post last dose of anti-tumor antibody therapy (including check point inhibitor) * Prior genetically modified cell therapy is allowed if not detectable at enrollment. * If no apheresis product or T cell product is available,≥ 6 weeks post last dose of myeloablative therapy and allogeneic or autologous stem cell transplant * Subjects who receive autologous stem cell infusion following non-myeloablative therapy are eligible once all other eligibility requirements are met * If no apheresis product or T cell product is available,≥ 7 days post last systemic corticosteroid therapy (physiologic replacement dosing is allowed) * If no apheresis product or T cell product is available, subjects with neuroblastoma must be ≥ 12 weeks from I131 MIBG therapy. * Adequate organ function * Adequate laboratory values * Patients of childbearing potential must agree to use highly effective contraception Exclusion Criteria: * Presence of active malignancy other than primary malignant solid tumor diagnosis * Current relevant CNS pathology * Presence of active GVHD, or receiving immunosuppressive therapy for treatment or prevention of GVHD within 4 weeks prior to enrollment * Presence of active severe infection * Presence of primary immunodeficiency syndrome * Receiving external beam radiation therapy at time of enrollment * Receiving any anti-cancer agents or chemotherapy * Pregnant or breastfeeding * Unwilling to provide consent/assent for participation in the study and 15 year follow up period * Presence of any condition that, in the opinion of the investigator, would prohibit the patient from undergoing treatment under this protocol
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：Estimate the maximum tolerated dose (MTD) or biologically effective dose and dose limiting toxicities (DLT), and describe the full toxicity profile of the two CAR T cell products · Type, frequency, severity, and duration of adverse events will be tabulated and summarized · 28 days；The number of successfully manufactured EGFR806 and EGFR806xCD19 CAR T cell products will be assessed · The number of successfully manufactured products will be measured · 28 Days；Establish the safety, defined by adverse events, of EGFR806-specific CAR T cell infusions (Arm A), and of dual transduced EGFR806xCD19 CAR T cell infusions (Arm B) · Type, frequency, severity, and duration of adverse events will be tabulated and summarized · 28 Days
次要终点：Number of Arm A and Arm B subjects with persistence of CAR T cells in the peripheral blood at each visit time point；Number of Arm A and Arm B subjects with persistence of CAR T cells in the bone marrow at each visit time point
自体CD4+和CD8+ T细胞经基因改造后表达EGFR 806CAR(2G)-EGFRt。
自体CD4+和CD8+ T细胞经基因改造后表达EGFR806CAR(2G)-EGFRt及CD19CAR(2G)-T2A-HER2tG。
这是一项Ⅰ期、开放标签、非随机研究，纳入复发或难治性非中枢神经系统（CNS）实体瘤儿童和青年，评估输注自体T细胞产品的安全性、可行性和疗效。研究者从受试者血液中获取T细胞并进行基因改造，使其表达EGFR特异性受体（嵌合抗原受体，CAR），以靶向并杀伤表达EGFR的实体瘤，同时表达选择/自杀标记EGFRt。EGFRt是一种与EGFR受体共同导入细胞的蛋白，可识别改造后的T细胞；必要时可作为标记清除这些细胞。 A组仅接受EGFR特异性CAR-T细胞；B组接受同时靶向EGFR和CD19的CAR-T细胞。研究假设，正常发挥抗原呈递作用的CD19阳性B细胞可促进CAR-T细胞扩增和持续存在。CD19受体含有另一种选择/自杀标记HERtG。 主要目标包括确定细胞产品的制备可行性、T细胞输注安全性、CAR-T最大耐受剂量、各产品完整毒性谱及改造细胞在体内的持续时间。受试者单次接受由CD4和CD8两种T细胞亚型组成的细胞产品，预期两种亚型共同发挥作用以提高治疗效果。次要目标包括检测患者体内改造细胞数量及其可检出时间，并量化各组抗肿瘤疗效。若受试者出现显著且可能危及生命的毒性（可临床控制的T细胞活性相关细胞因子释放综合征除外），将给予西妥昔单抗（靶向EGFRt）或曲妥珠单抗（靶向HER2tG），评估相应标记能否作为有效自杀机制清除回输的T细胞产品。
This is a phase I, open-label, non-randomized study that will enroll pediatric and young adult research participants with relapsed or refractory non-CNS solid tumors to evaluate the safety, feasibility, and efficacy of administering T cell products derived from the research participant's blood that have been genetically modified to express a EGFR-specific receptor (chimeric antigen receptor, or CAR) that will target and kill solid tumors that express EGFR and the selection-suicide marker EGFRt. EGFRt is a protein incorporated into the cell with our EGFR receptor which is used to identify the modified T cells and can be used as a tag that allows for elimination of the modified T cells if needed. On Arm A of the study, research participants will receive EGFR-specific CAR T cells only. On Arm B of the study, research participants will receive CAR T cells directed at EGFR and CD19, a marker on the surface of B lymphocytes, following the hypothesis that CD19+ B cells serving in their normal role as antigen presenting cells to T cells will promote the expansion and persistence of the CAR T cells. The CD19 receptor harbors a different selection-suicide marker, HERtG. The primary objectives of the study will be to determine the feasibility of manufacturing the cell products, the safety of the T cell product infusion, to determine the maximum tolerated dose of the CAR T cells products, to describe the full toxicity profile of each product, and determine the persistence of the modified cell in the subject's body on each arm. Subjects will receive a single dose of T cells comprised of two different subtypes of T cells (CD4 and CD8 T cells) felt to benefit one another once administered to the research participants for improved potential therapeutic effect. The secondary objectives of this protocol are to study the number of modified cells in the patients and the duration they continue to be at detectable levels. The investigators will also quantitate anti-tumor efficacy on each arm. Subjects who experience significant and potentially life-threatening toxicities (other than clinically manageable toxicities related to T cells working, called cytokine release syndrome) will receive infusions of cetuximab (an antibody commercially available that targets EGFRt) or trastuzumab (an antibody commercially available that targets HER2tG) to assess the ability of the EGFRt on the T cells to be an effective suicide mechanism for the elimination of the transferred T cell products.
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