肿瘤细胞治疗研究
英文原题：Activated T Lymphocytes Expressing CARs, Relapsed CD19+ Malignancies Post-Allo HSCT(CARPASCIO)
这是一项 I 期注册临床试验，评估 CD19T 细胞治疗淋巴瘤、急性淋巴细胞白血病、慢性淋巴细胞白血病的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 7 例。试验地点：美国 · 休斯顿（共 2 个中心）。登记号：NCT02050347。
不限性别
细胞采集阶段纳入标准： * A组：接受异体HSCT的CD19阳性B细胞ALL；或B组：接受异体HSCT的CD19阳性B细胞CLL或NHL； * 预期寿命≥12周； * 已确定适合造血干细胞移植的供者。 治疗阶段纳入标准： * 不限性别或年龄：A组为接受异体HSCT的CD19阳性B细胞ALL患者；B组为接受异体HSCT的CD19阳性B细胞CLL或NHL患者； * 移植时存在残留病灶（大肿块或微小残留），或移植后复发；证据包括PCR阳性、特定细胞遗传学异常、流式细胞术发现异常细胞群，或骨髓活检/外周血原始细胞增多。微小残留病（MRD）包括移植后评估中检出以下任一情况：移植前白血病细胞已记录的白血病特异性标志物（如t(9;22)或t(4;11)）；该患者已知的疾病标志性免疫球蛋白重排；移植后白血病特异性表型≥0.01%；任意程度的混合供者嵌合； * 预期寿命≥6周； * Karnofsky/Lansky评分≥50%； * 胆红素≤ULN的2倍；AST≤ULN的3倍；估算GFR>50 mL/min；血红蛋白≥7.0（可采用输血后数值）；室内空气下血氧饱和度>90%； * 有性生活者同意研究期间及ATL输注后6个月内采用高效避孕方法，男性伴侣须使用安全套； * 有可用的异体活化外周血T细胞产品，流式细胞术测得CD19.CAR-CD28ζ表达≥15%（细胞剂量按总细胞数而非单个抗白血病细胞数计算）； * 入组前1个月内未接受其他试验性抗肿瘤治疗； * 患者或法定监护人签署知情同意书。 排除标准：严重并发感染；存在>Ⅱ级GVHD；妊娠或哺乳；对含鼠源蛋白制品有超敏反应史；目前因治疗GVHD而使用皮质类固醇（泼尼松或等效剂量>0.5 mg/kg/日）。
Inclusion Criteria: PROCUREMENT * Group A: CD19+ B-ALL undergoing allogeneic HSCT or Group B: CD19+ B cell CLL or NHL undergoing allogeneic HSCT * Life expectancy of ≥12 weeks. * Patient has an appropriate donor identified for hematopoietic stem cell transplantation TREATMENT * Any patient regardless of sex or age with CD19+ B-ALL undergoing allogeneic HSCT (Group A) OR any patient regardless of sex or age with CD19+ B-CLL or NHL undergoing allogeneic HSCT (Group B) * Residual disease at the time of transplant (bulky or minimal) or post transplant relapse as evidenced by PCR positivity, specific cytogenetic abnormalities, an abnormal population on flow cytometry or increased blasts on bone marrow biopsy or in the peripheral blood. MRD will be defined as detection in blood or marrow of any of the following: * Any leukemia specific marker (such as t(9:22) or t(4:11)) documented in the patient's leukemia cells pre transplant on a post transplant evaluation. * An immune globulin rearrangement known to be a disease marker for this patient post transplant. * A leukemia specific phenotype post transplant at a level of ≥ 0.01% * Mixed donor chimerism (any level) * Life expectancy ≥ 6 weeks * Karnofsky/Lansky score ≥ 50%. * Bilirubin ≤ 2 times the upper limit of normal. * AST ≤ 3 times the upper limit of normal. * Estimated GFR \> 50 mL/min * Hgb ≥ 7.0 (can be a transfused value) * Pulse oximetry of \> 90% on room air * Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 6 months after ATL infusion. The male partner should use a condom. * Available allogeneic activated peripheral blood T cell products with \>=15% expression of CD19.CAR-CD28ζ determined by flow cytometry (cell dose is based on total cell numbers and not individual antileukemic cell numbers). * No other investigational antitumor therapy for one month prior to entry in this study. * Patients or legal guardians must sign an informed consent. Exclusion Criteria: * Severe intercurrent infection. * Evidence of GVHD \> grade II. * Pregnant or lactating. * History of hypersensitivity reactions to murine protein-containing products. * Currently taking corticosteroids (\>0.5 mg/kg/day prednisone or equivalent) for therapy of GVHD.
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 · Toxicity is evaluated using CTCAE, version 4.0. Dose limiting toxicity (DLT) will be defined as any of the following that is NOT (1) pre-existing, or (2) due to infection (to which patients with CLL and NHL are predisposed), or (3) due to underlying malignancy, and that may, after consultation with the FDA when indicated, be considered possibly, probably, or definitely related to the study cellular products:
* Development of Grade III-IV GVHD or Grade II GVHD unresponsive to front line treatment;
* Non-hematologic DLT is any grade 3 or grade 4 non-hematologic toxicity, including allergic reactions to T cell infusions.
* Hematologic DLT is defined as any grade 4 hematologic toxicity, including secondary graft failure (as defined per protocol).
* Patients with evidence of bone marrow disease (metastases or diffuse infiltration) are not evaluable for hematologic dose limiting toxicity. · 6 weeks
次要终点：Number of patients with tumor response；Frequency of T cell products
有残留或复发B细胞ALL且具有HLA匹配亲缘供者的患者，接受剂量递增1的CD19.CAR-CD28Z T细胞。
患有其他B细胞恶性肿瘤且具有HLA匹配亲缘供者的患者，接受剂量递增1的CD19.CAR-CD28Z T细胞。
有残留或复发B细胞ALL且供者为非亲缘或HLA不匹配的患者，接受剂量递增2的CD19.CAR-CD28Z T细胞。
患有其他B细胞恶性肿瘤且供者为非亲缘或HLA不匹配的患者，接受剂量递增2的CD19.CAR-CD28Z T细胞。
患者患有非霍奇金淋巴瘤（NHL）、急性淋巴细胞白血病（ALL）或慢性淋巴细胞白血病（CLL），这些疾病经治疗（包括现有最佳治疗）后复发或未缓解。目前尚无标准治疗，因此研究邀请患者参加使用特殊免疫细胞的基因转移研究。 机体通过多种方式抵抗感染和疾病，但单一方式似乎不足以对抗癌症。本研究尝试结合抗体和T细胞，希望二者协同发挥作用。抗体和T细胞均已用于癌症治疗并显示出希望，但尚不足以治愈大多数患者。T细胞可以杀伤肿瘤细胞，但数量通常不足以清除全部肿瘤；研究者可从患者血液中采集T细胞，在实验室扩增后再回输。 本研究使用抗CD19抗体。CD19是癌细胞表面的物质，抗CD19抗体可与癌细胞结合，曾用于治疗淋巴瘤和白血病。本研究将抗CD19抗体改造后连接到T细胞上；这种抗体与T细胞连接形成嵌合受体。T细胞还表达CD28，以刺激T细胞并延长其存活。 患者来源的CD19/CD28嵌合受体T细胞已显示出抗淋巴瘤和白血病活性。本研究将评估以健康干细胞供者为来源制备这些细胞是否疗效更佳；若无法采集供者血液，则采集受试者自身血液制备CD19/CD28嵌合受体T细胞。这些细胞为尚未获美国FDA批准的试验性产品。研究旨在确定安全的最大剂量，了解细胞在体内的持续时间及副作用，并评估其是否可能帮助供者干细胞移植后的淋巴瘤或白血病患者。
Patients have a type of lymph gland cancer called Non-Hodgkin Lymphoma (NHL), acute lymphocytic leukemia (ALL) or chronic lymphocytic leukemia (CLL) (these diseases will be referred to as "lymphoma" or "leukemia"). The lymphoma or leukemia has come back or has not gone away after treatment (including the best treatment known for these cancers). Because there is no standard treatment for this cancer at this time, subjects are asked to volunteer to be in a gene transfer research study using special immune cells. The body has different ways of fighting infection and disease. No one way seems perfect for fighting cancers. This research study combines two different ways of fighting disease, antibodies and T cells, hoping that they will work together. 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. T cells can kill tumor cells but there normally are not enough of them to kill all the tumor cells. Some researchers have taken T cells from a person's blood, grown more of them in the laboratory and then given them back to the person. The antibody used in this study is called anti-CD19. This antibody sticks to cancer cells because of a substance on the outside of these cells called CD19. CD19 antibodies have been used to treat people with lymphoma and leukemia. For this study, the CD19 antibody has been changed so that instead of floating free in the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. The T lymphocytes will also contain CD28, which stimulates T cells and makes them last longer. Treatment with CD19/CD28 chimeric receptor-T cells has had activity against lymphoma and leukemia when the cells are made from the patients affected by these diseases. In this study, investigators are going to see if this treatment works even better when they make these cells from a healthy stem cell donor. If investigators are not able to collect blood from the stem cell donor, they will collect blood from the subject to make the CD19/CD28 chimeric receptor-T cells. These CD19/CD28 chimeric receptor T cells are investigational products not approved by the FDA. The purpose of this study is to find the biggest dose of chimeric T Cells that is safe, to see how long T cells with this chimeric receptor last, to learn what the side effects are, and to see whether this therapy might help people with lymphoma or leukemia after a stem cell transplantation from a donor.
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