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

描述(由申请人提供)： 大多数晚期B系恶性肿瘤患者超过首次复发，随后达到缓解状态，或至少达到微小残留疾病状态，符合异基因造血干细胞移植(HSCT)的条件。脐带血(UCB)作为异基因造血干细胞(HSC)替代来源的引入是异基因HSCT领域的一个重大进展。脐带血移植(UCBT)的主要优点包括(I)异体移植物的快速获取，(Ii)增加 为少数族裔患者寻找配型，(Iii)对不那么严格的人类白细胞抗原配型的要求，以及(Iv) 移植物抗宿主病(GVHD)发生率降低。然而，复发仍然是UCBT治疗潜力的主要障碍。过继转移表达第二代CD19特异性嵌合抗原受体(CAR)的T细胞已被证明可以治愈一些晚期B细胞恶性肿瘤患者。这项建议试图在人类首个针对B细胞恶性肿瘤的临床第一阶段方案的背景下，应用这种过继免疫疗法来防止异基因脐带血移植后的复发。Clinica Impact是基于靶向CD19的，CD19是一种表达在恶性B细胞上的B系抗原。将使用睡美人(SB)DNA质粒转座子/转座酶系统，这(I)避免了其他研究人员目前正在制造用于嵌合抗原受体(CAR)转基因基因转移的临床级慢病毒的问题，以及(Ii)与使用临床级重组逆转录和慢病毒转导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CD19的人工抗原提呈细胞(AAPC)上快速、选择性地增殖到临床所需的数量。这避免了制造转导T细胞的临床级重组逆转录病毒所需的时间和费用。这可以通过少量的脐带血来实现，以避免损害受者的造血。这项建议旨在：目的#1，输注分级剂量的CD19特异的转基因T细胞，并评估异基因脐带血移植后晚期B系恶性肿瘤患者的联合免疫疗法；目的#2，承担主要目标，以确定单剂脐带血来源的转基因T细胞的安全性、可行性和持久性。患者内部的给药方案将确定T细胞的输入量是否会改变嵌合抗原受体阳性T细胞的持久性(预计会影响其治疗潜力)#3、进行次级目标以确定对转基因的免疫应答(S)；CAR T细胞的贩运；输注T细胞的寡克隆亚群的发展(S)；具有效应器记忆、中央记忆、干细胞样和/或幼稚免疫表型的转基因T细胞的出现；以及CD19重定向的效应器功能的维持。

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.