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

描述(申请人提供)：目前，对于异基因造血干细胞移植(HSCT)后的疾病复发还没有有效的治疗方法。T细胞治疗可以利用与化疗和放射治疗无关的机制来靶向恶性肿瘤，具有无重叠且毒性一般较轻的特点。因此，我们正在研究过继免疫治疗作为一种策略，以增强异基因HSCT后的移植物抗肿瘤(GVT)效应。然而，这一方法受到了以下问题的限制：难以确定大量HLA等位基因的免疫原性表位，T细胞对白血病相关抗原的耐受性，以及难以及时制造患者特异性T细胞。作为一种替代策略，我们建议使用基因修饰的T细胞来表达嵌合抗原受体(CAR)，该嵌合抗原受体(CAR)是不依赖于MHC的所需肿瘤抗原。为了针对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定向到B细胞谱系限制的细胞表面分子CD19。CD19在大多数B系白血病或淋巴瘤细胞上表达，但在造血干细胞和非造血细胞上不表达。基因修饰的CD19特异性T细胞通过与CD19结合的嵌合CD3-1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来开启一项I期临床试验(BB-IND 11411)，在复发的滤泡性淋巴瘤患者中输注自体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，将来自脐带血(UCB)的预先准备好的CD19特异性T细胞输注于异基因HSCT后复发的B细胞白血病/淋巴瘤患者。值得注意的是，这项试验将是(I)异基因造血干细胞移植后首次在人类体内注入CD19特异性T细胞，(Ii)首次注入表达第二代CAR的T细胞，该T细胞能够提供完全有效的T细胞激活信号(通过嵌合CD3-β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细胞在体内的分布及其激活状态，这是放射基因治疗的一个例子。我们假设，先验一代的同质人群的脐带血来源的不匹配的CD19特异性T细胞克隆的银行将允许T细胞在一个几乎没有生存机会的患者群体中以安全和及时的方式输注。T细胞分离、基因修改和扩增将遵循MDACC的标准操作程序，T细胞剂量将在我们的良好制造工艺(GMP)设施中按照FDA授权的主细胞库的质量控制/保证标准生产。LAV语言：T细胞将被开发出来，它可以摧毁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.