UCB-DERIVED CD19-SPECIFIC T CELLS FOR UNIVERSAL TREATMENT OF B-CELL MALIGNANCY

描述（申请人提供）：目前，对于同种异体造血干细胞移植（HSCT）后的疾病复发没有有效的治疗方法。t细胞治疗可以使用独立于化疗放疗的机制靶向恶性肿瘤，具有不重叠和一般轻微的毒性。因此，我们正在研究过继性免疫治疗作为增强同种异体造血干细胞移植后移植物抗肿瘤（GVT）效应的策略。然而，由于大量HLA等位基因的免疫原性表位描述问题、T细胞对白血病相关抗原的耐受性以及及时制造患者特异性T细胞的困难，这种方法受到了限制。作为一种替代策略，我们建议使用基因修饰的T细胞来表达一种嵌合抗原受体（CAR）特异性的所需肿瘤抗原，不依赖于MHC。为了靶向B细胞恶性肿瘤，我们设计了一种CAR，它将T细胞的抗原特异性重新定向到B细胞谱系限制细胞表面分子CD19上。CD19在大多数b系白血病或淋巴瘤细胞中表达，但在造血干细胞和非造血细胞中不表达。基因修饰的CD19特异性T细胞通过CAR结合CD19的嵌合CD3-^被激活，导致抗原依赖性细胞因子的产生、杀伤和增殖。这些临床前数据被用于开启一项I期临床试验（BB-IND 11411），该试验在复发的滤泡性淋巴瘤患者中注入自体cd19特异性T细胞（表达第一代CAR）。在这项拨款中，我们提出了一项新的临床试验，在异基因造血干细胞移植后复发的b系白血病/淋巴瘤患者中注入来自脐带血（UCB）的预先制备的cd19特异性T细胞。值得注意的是，该试验将是(i)同种异体造血干细胞移植后“首次在人体中”输注cd19特异性T细胞，（ii）首次输注表达第二代CAR的T细胞，能够提供完全有效的T细胞激活信号（通过嵌合CD3-¿；和CD28），以及（iii）首次通过正电子发射断层扫描（PET）成像转基因T细胞的分布及其在体内的激活状态，这是放射基因治疗的一个例子。我们假设，先天产生的来自ucb的同源hla不匹配CD19特异性T细胞克隆库将允许在生存机会很小的患者群体中以安全及时的方式输注T细胞。t细胞分离、基因修饰和扩增将按照MDACC的标准操作程序进行，t细胞剂量将按照FDA对主细胞库规定的质量控制/保证标准在我们的良好生产工艺（GMP）设施中生产。Lav语言：T细胞将被开发出来，可以摧毁b系疾病。

DESCRIPTION (provided by applicant): Currently, there are no effective treatments for disease recurrence following allogeneic hematopoietic stem- cell transplant (HSCT). T-cell therapy can target malignancies using mechanisms independent of chemo- radiotherapy, with non-overlapping and generally mild toxicities. Thus, we are investigating adoptive immunotherapy as a strategy to augment the graft-versus-tumor (GVT) effect after allogeneic HSCT. However, this approach has been limited by problems delineating immunogenic epitopes for a large number of HLA alleles, T-cell tolerance to leukemia-associated antigens, and the difficulty of manufacturing patient- specific T cells in a timely manner. As an alternative strategy, we propose to use T cells genetically modified to express a chimeric antigen receptor (CAR) specific a desired tumor antigen independent of MHC. To target B-cell malignancies, we have designed a CAR which re-directs the antigen-specificity of T cells to the B cell lineage-restricted cell-surface molecule CD19. CD19 is expressed on the majority of B-lineage leukemia or lymphoma cells, but is absent on hematopoietic stem cells and non-hematopoietic cells. Genetically modified CD19-specific T cells are activated via chimeric CD3-^ upon CAR binding CD19, resulting in antigen-dependent cytokine production, killing and proliferation. These preclinical data were used to open a Phase I clinical trial (BB-IND 11411) infusing autologous CD19-specific T cells (expressing the first-generation CAR) in patients with relapsed follicular lymphoma. In this grant, we propose a new clinical trial to infuse pre-prepared CD19-specific T cells derived from umbilical cord blood (UCB) in patients with relapsed B-lineage leukemia/lymphoma after allogeneic HSCT. Significantly, this trial will be (i) the "first-in- human" infusion of CD19-specific T cells after allogeneic HSCT, (ii) the first to infuse T cells expressing a second-generation CAR capable of providing a fully-competent T-cell activation signal (through chimeric CD3-¿; and CD28), and (iii) the first to image distribution of genetically modified T cells and their activation status in vivo by positron emission tomography (PET), an example of radio-gene-therapy. We hypothesize that the a priori generation of banks of a homogenous population of UCB-derived HLA-unmatched CD19- specific T-cell clones will permit infusion of T cells in a safe and timely manner in a patient population with little chance of survival. T-cell isolation, genetic modification, and expansion will follow Standard Operating Procedures at MDACC, and T-cell doses will be manufactured in our Good Manufacturing Process (GMP) facility in accordance with quality control/assurance standards mandated by the FDA for a master cell bank. Lav language: T cells will be developed which can destroy B-lineage disease.