肿瘤细胞治疗研究
英文原题：Genetically Modified T-cell Infusion Following Peripheral Blood Stem Cell Transplant in Treating Patients With Recurrent or High-Risk Non-Hodgkin Lymphoma
这是一项 I 期注册临床试验，评估自体 T 细胞治疗淋巴瘤、非霍奇金淋巴瘤、B 细胞淋巴瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 30 例。试验地点：美国 · 杜阿尔特（共 1 个中心）。登记号：NCT01815749。
不限性别 · ≥ 18 Years
纳入标准： * 研究参与者为有造血干细胞移植（HSCT）评估指征、确诊中级别B细胞非霍奇金淋巴瘤（如弥漫大B细胞淋巴瘤[DLBCL]、套细胞淋巴瘤[MCL]或转化型淋巴瘤），且既往治疗后复发/进展，或在首次缓解期确认存在高危疾病的患者。 * 入组时Karnofsky体能状态评分≥70%，预期寿命≥16周。 * 有生育能力的女性及男性须同意在入组前及整个研究参与期结束后6个月内采取适当避孕措施（激素或屏障避孕法，或禁欲）。若女性在研究期间妊娠或怀疑妊娠，应立即告知治疗医生。 * 希望之城（COH）病理复核确认，研究参与者的诊断材料与其中级别B细胞非霍奇金淋巴瘤病史相符（如DLBCL、MCL或转化型淋巴瘤）。 * 有生育能力女性的血清妊娠试验阴性。 * 研究参与者有接受自体干细胞移植评估的指征。 * 所有患者均须能够理解并愿意签署书面知情同意书。 接受自体清髓性移植并以造血祖细胞（HPC）回输支持的资格： * 研究参与者符合COH现行造血细胞移植标准操作政策、程序及方案所述自体移植候选者的全部标准临床参数。 * 患者评估及造血细胞移植（HCT）候选选择或暂缓标准。 * 研究参与者计划接受标准化疗预处理方案，例如环磷酰胺、卡莫司汀、依托泊苷（CBV），或卡莫司汀、依托泊苷、阿糖胞苷、美法仑（BEAM）。 * 研究参与者有冷冻保存的未筛选HPC(A)产品，其中CD34+细胞至少为3×10^6/kg。 * 研究参与者在挽救治疗后无疾病进展证据。 基因改造自体T细胞输注时的资格标准： * 研究参与者有已放行的冷冻保存T细胞产品。 * 研究参与者已接受自体HPC(A)治疗程序。 * 不需要补充氧气或机械通气；室内空气下血氧饱和度≥90%。 * 不需要升压药支持，且无有症状的心律失常。 * 无急性肾衰竭或透析需求，肌酐<1.6；总胆红素≤5.0。 * 研究参与者无具有临床意义的脑病或新发局灶性神经功能缺损。 * 无未控制活动性感染的临床证据。 排除标准： * 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感染；入组前4周内检测显示HIV血清阳性；有活动性感染体征或症状、血培养阳性或影像学感染证据。 * 正在接受其他研究性药物，或同时接受生物治疗、化疗或放疗。 * 曾对与西妥昔单抗化学或生物组成相似的化合物发生过敏反应。 * 已知脑转移，包括中枢神经系统（CNS）受累、脑实质或软脑膜受累。 * 存在其他恶性肿瘤，或入组前5年内有既往恶性肿瘤史；但在5年内接受根治性治疗的患者仍可入组。非黑色素瘤皮肤肿瘤及宫颈原位癌不适用此排除标准。 * 研究参与者无法理解本方案的基本内容和/或参加该I期/II期研究的风险与获益；可由法定监护人代为理解和同意。 * 有异基因HSCT或既往自体HSCT史。 * 按COH标准诊疗实践，存在任何清髓性HSCT常见禁忌证。 * 依赖皮质类固醇。 * 活动性自身免疫性疾病且需要全身免疫抑制治疗。 * 研究者认为可能无法遵守本研究安全监测要求的患者。
Inclusion Criteria: * Research participants enrolled are patients with an indication to be considered for HSCT, who are diagnosed with intermediate grade B-cell NHL (e.g., DLBCL, MCL or transformed NHL), and that have either recurrence/progression following prior therapy, or verification of high-risk disease in first remission * Karnofsky performance status of \>= 70% and a life expectancy \>= 16 weeks at time of enrollment * 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) pathology review confirms that research participant's diagnostic material is consistent with the history of intermediate grade B-cell NHL (e.g., DLBCL, MCL or transformed NHL) * Negative serum pregnancy test for women of childbearing potential * Research participant has an indication to be considered for autologous stem cell transplantation * All patients must have the ability to understand and the willingness to sign a written informed consent ELIGIBILITY TO UNDERGO AUTOLOGOUS MYELOABLATIVE TRANSPLANTATION WITH HEMATOPOETIC PROGENITOR CELL (HPC)A RESCUE * Research participant meets all standard clinical parameters for candidates of autologous transplant as described in the current COH Hematopoietic Cell Transplant Standard Operating Policies, Procedures and Protocols * Patient Evaluation \& Selection or Deferral for hematopoietic cell transplantation (HCT) * Research participant is scheduled to receive a standard chemotherapy-based conditioning regimen, such as cyclophosphamide, carmustine, etoposide (CBV) or carmustine, etoposide, cytarabine, melphalan (BEAM) * Research participant has a cryopreserved unselected HPCA product of at least 3 x 10\^6/kg CD34+ cells * Research participant does not have evidence of disease progression after salvage therapy ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS * Research participant has a released cryopreserved T cell product * Research participant has undergone an autologous HPC(A) procedure * Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation of 90% or higher on room air * Not requiring pressor support, not having symptomatic cardiac arrhythmias * Lack of acute renal failure/requirement for dialysis, as evidenced by creatinine \< 1.6 - Total bilirubin =\< 5.0 * Research participant without clinically significant encephalopathy/new focal deficits * No clinical evidence of uncontrolled active infections process Exclusion Criteria: * Research participants with any uncontrolled illness including ongoing or active infection; research participants with known active hepatitis B or C infection; research participants who are human immunodeficiency virus (HIV) seropositive based on testing performed within 4 weeks of enrollment; research participants with any signs of symptoms of active infection, positive blood cultures or radiological evidence of infections * Research participants receiving any other investigational agents, or concurrent biological, chemotherapy or radiation therapy * History of allergic reactions attributed to compounds of similar chemical or biologic composition to cetuximab * Research participants with known brain metastases (central nervous system \[CNS\] involvement or parenchymal or leptomeningeal involvement) * Research participants with presence of other malignancy or history of prior malignancy within 5 years of study entry; although patients treated with curative intent within 5 year are eligible; this exclusion rule does not apply to non-melanoma skin tumors and in-situ cervical cancer * Failure of research participant to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase I/II study; a legal guardian may substitute for the research participant * History of allogeneic HSCT or prior autologous HSCT * Any standard contraindications to myeloablative HSCT per standard of care practices at COH * Dependence on corticosteroids * Active autoimmune disease requiring systemic immunosuppressive therapy * Research participants will be excluded, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
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：Adverse events attributed to Tcm adoptive transfer as reported using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 · Tables will be created to summarize all toxicities and side effects by dose, course, organ, and severity. · Up to 15 years；MTD of CD19-CAR-specific/truncated EGFR lentiviral vector-transduced autologous T cells based on dose limiting toxicities · Graded according to the NCI CTCAE version 4.0. · Up to day 28
次要终点：Engraftment of the transferred T cell products；CD19+ B cell precursors in the peripheral blood as a surrogate for the in vivo effector function of transferred CD19-specific T cells
患者按当前标准操作政策接受细胞减灭化疗及非格司亭和/或普乐沙福动员，以采集自体干细胞。自第-7天起按机构标准接受清髓性预处理方案，并于第0天进行造血干细胞移植。患者于第2或第3天静脉输注经慢病毒载体转导、表达CD19特异性CAR及截短EGFR的自体T细胞（若患者尚不符合条件，可推迟至第45天）。移植后≥100天出现疾病进展且未发生剂量限制性毒性（DLT）的患者，可选择再次接受一次T细胞输注。
这项I期试验研究外周血干细胞移植后输注基因改造T细胞治疗复发或高危非霍奇金淋巴瘤患者的副作用及最佳剂量。干细胞移植前给予化疗有助于抑制癌细胞生长。将健康供者的干细胞输注给患者后，可能帮助患者骨髓生成干细胞、红细胞、白细胞及血小板。有时移植的供者细胞会对患者正常细胞产生免疫反应。移植前从供者细胞中去除T细胞可能有助于避免这种情况。之后再输注供者T细胞（供者淋巴细胞输注），可能使患者免疫系统识别并清除残留癌细胞，产生所谓的移植物抗肿瘤效应。
This phase I trial studies the side effects and best dose of genetically modified T-cells following peripheral blood stem cell transplant in treating patients with recurrent or high-risk non-Hodgkin lymphoma. Giving chemotherapy before a stem cell transplant helps stop the growth of cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Removing the T cells from the donor cells before transplant may stop this from happening. Giving an infusion of the donor's T cells (donor lymphocyte infusion) later may help the patient's immune system see any remaining cancer cells as not belonging in the patient's body and destroy them (called graft-versus-tumor effect)
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