Phase 1 Study of Umbilical Cord Blood-Derived T Cells in Malignant B Cells

恶性 B 细胞中脐带血衍生 T 细胞的 1 期研究

• 批准号: 8417456
• 负责人: Laurence J.N. Cooper
• 金额: $ 20万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417456
• 关键词: Phase; Study; Umbilical; Cord; Blood

DESCRIPTION (provided by applicant): Most patients with advanced B-lineage malignancies who are beyond first relapse and subsequently attain a state of remission, or at least a state of minimal-residual disease, are eligible for allogeneic hematopoietic stem-cell transplantation (HSCT). The introduction of umbilical cord blood (UCB) as an alternative source of allogeneic hematopoietic stem cells (HSC) for patients without a suitable human leukocyte antigen (HLA)-matched donor is a major advance for the field of allogeneic HSCT. Major advantages of umbilical cord blood transplantation (UCBT) include (i) rapid procurement of the allograft, (ii) increased likelihood of finding a match for a minority patient, (iii) requirement for less-stringent HLA matching, and (iv) decreased incidence of graft-versus-host disease (GVHD). However, relapse remains a major barrier to the therapeutic potential of UCBT. The adoptive transfer of T cells expressing a second generation CD19-specific chimeric antigen receptor (CAR) has been shown to cure some patients with advanced B-cell malignancies. This proposal seeks to apply this adoptive immunotherapy to prevent relapse after allogeneic umbilical cord blood transplantation in the setting of a first-in-human clinical Phase 1 protocol that targets B-cell malignancies. The clinica impact is based upon targeting CD19, a B-lineage antigen expressed on malignant B cells. The Sleeping Beauty (SB) DNA plasmid transposon/transposase system will be used, which (i) avoids current problems other investigators are currently experiencing manufacturing clinical-grade lentivirus for gene transfer of the chimeric antigen receptor (CAR) transgene, and (ii) by using a non-viral system reduces cost compared to transducing T cells with clinical-grade recombinant retro- and lentivirus. Umbilical cord blood-derived CAR positive T cells can be rapidly and selectively propagated to clinically-sufficient numbers on designer artificial antigen presenting cells (aAPC) expressing CD19. This avoids the time and expense needed to manufacture clinical-grade recombinant retrovirus to transduce T cells. This can be achieved from small amounts of UCB to avoid compromising hematopoiesis in the recipient. This proposal seeks to: Aim #1, infuse graded doses of CD19-specific, genetically modified, T cells and evaluate combination immunotherapy in patients with advanced B-lineage malignancies after allogeneic UCBT; Aim #2, undertake the primary objectives to establish safety, feasibility, and persistence of a single dose of UCB-derived genetically modified T cells. An intra-patient dosing scheme will determine whether the amount of T cells infused alters persistence of chimeric antigen receptor positive T cells which is predicted to impact their therapeutic potential Aim #3, undertake secondary objectives to determine immune response(s) to the transgenes; trafficking of CAR+ T cells; development of oligoclonal sub-population(s) of infused T cells; emergence of genetically modified T cells with effector memory, central memory, stem-cell-like, and/or naive immunophenotypes; and maintenance of CD19- redirected effector functions.

描述（由申请人提供）： 大多数晚期 B 系恶性肿瘤患者如果超过首次复发并随后达到缓解状态或至少达到微小残留疾病状态，则有资格接受同种异体造血干细胞移植 (HSCT)。对于没有合适的人类白细胞抗原 (HLA) 匹配供体的患者，引入脐带血 (UCB) 作为同种异体造血干细胞 (HSC) 的替代来源，是同种异体 HSCT 领域的重大进步。脐带血移植 (UCBT) 的主要优点包括 (i) 快速获得同种异体移植物，(ii) 增加移植的可能性 为少数族裔患者找到匹配，(iii) 要求不太严格的 HLA 匹配，以及 (iv) 移植物抗宿主病（GVHD）的发生率降低。然而，复发仍然是 UCBT 治疗潜力的主要障碍。表达第二代 CD19 特异性嵌合抗原受体 (CAR) 的 T 细胞的过继转移已被证明可以治愈一些患有晚期 B 细胞恶性肿瘤的患者。该提案旨在在针对 B 细胞恶性肿瘤的首次人体临床 1 期方案中应用这种过继免疫疗法来预防同种异体脐带血移植后的复发。临床影响基于针对 CD19，这是一种在恶性 B 细胞上表达的 B 谱系抗原。将使用睡美人 (SB) DNA 质粒转座子/转座酶系统，该系统 (i) 避免了其他研究人员目前在制造用于嵌合抗原受体 (CAR) 转基因的基因转移的临床级慢病毒时遇到的问题，以及 (ii)与使用临床级重组逆转录病毒和慢病毒转导 T 细胞相比，使用非病毒系统可降低成本。脐带血来源的 CAR 阳性 T 细胞可以在表达 CD19 的人工抗原呈递细胞 (aAPC) 上快速、选择性地增殖至临床上足够的数量。 这避免了制造临床级重组逆转录病毒来转导 T 细胞所需的时间和费用。这可以通过少量的 UCB 来实现，以避免损害受体的造血功能。该提案旨在：目标#1，输注分级剂量的 CD19 特异性转基因 T 细胞，并评估同种异体 UCBT 后晚期 B 系恶性肿瘤患者的联合免疫治疗；目标#2，主要目标是确定单剂量 UCB 衍生的转基因 T 细胞的安全性、可行性和持久性。患者体内剂量方案将确定输注的 T 细胞数量是否会改变嵌合抗原受体阳性 T 细胞的持久性，预计这会影响其治疗潜力。目标 #3，承担次要目标，以确定对转基因的免疫反应； CAR+ T 细胞的贩运；输注 T 细胞寡克隆亚群的发育；具有效应记忆、中枢记忆、干细胞样和/或初始免疫表型的转基因 T 细胞的出现；和维持 CD19 重定向效应器功能。