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: 8732611
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732611
• 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系恶性肿瘤患者在首次复发后，随后达到缓解状态，或至少是最小残留疾病状态，有资格接受异基因造血干细胞移植（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）作为异基因造血干细胞（HSC）的替代来源是异基因HSCT领域的重大进展。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）增加移植物的可能性。 为少数患者找到匹配，（iii）要求不太严格的HLA匹配，和（iv） 降低移植物抗宿主病（GVHD）的发生率。然而，复发仍然是UCBT治疗潜力的主要障碍。表达第二代CD 19特异性嵌合抗原受体（CAR）的T细胞的过继转移已显示治愈一些患有晚期B细胞恶性肿瘤的患者。该提案旨在应用这种过继性免疫疗法，以预防在针对B细胞恶性肿瘤的首次人体临床1期方案中同种异体脐带血移植后的复发。临床影响基于靶向CD 19，一种在恶性B细胞上表达的B系抗原。将使用睡美人（SB）DNA质粒转座子/转座酶系统，其（i）避免了其他研究人员目前正在经历的用于嵌合抗原受体（CAR）转基因转移的临床级慢病毒的生产问题，以及（ii）与用临床级重组逆转录病毒和慢病毒转导T细胞相比，使用非病毒系统降低了成本。脐带血来源的CAR阳性T细胞可以在表达CD 19的设计者人工抗原呈递细胞（aAPC）上快速和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到CD 3 T细胞所需的时间和费用。这可以通过少量的UCB来实现，以避免损害接受者的造血。这项建议旨在：目的#1，输注分级剂量的CD 19特异性、遗传修饰的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疗法;目的#2，承担主要目标，以确定单剂量UCB衍生的遗传修饰的T细胞的安全性、可行性和持久性。患者内给药方案将确定输注的T细胞的量是否改变嵌合抗原受体阳性T细胞的持久性，这被预测会影响其治疗潜力。具有效应记忆、中枢记忆、干细胞样和/或幼稚免疫表型的遗传修饰的T细胞的出现;以及CD 19重定向的效应功能的维持。