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

描述（由申请人提供）：目前，对于异基因造血干细胞移植（HSCT）后的疾病复发没有有效的治疗方法。T细胞疗法可以使用独立于化学-放射疗法的机制靶向恶性肿瘤，具有非重叠和通常轻微的毒性。因此，我们正在研究过继免疫治疗作为一种策略，以增加移植物抗肿瘤（GVT）效应后同种异体HSCT。然而，这种方法受到以下问题的限制：描绘大量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，我们提出使用经遗传修饰的T细胞来表达特异性嵌合抗原受体（CAR），所述嵌合抗原受体特异于所需的肿瘤抗原，而不依赖于MHC。为了靶向B细胞恶性肿瘤，我们设计了一种CAR，其将T细胞的抗原特异性重定向至B细胞谱系限制的细胞表面分子CD 19。CD 19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存在。经遗传修饰的⑶ 19特异性T细胞在CAR结合⑶ 19时经由嵌合⑶ 3-γ活化，导致抗原依赖性细胞因子产生、杀伤和增殖。这些临床前数据用于启动一项I期临床试验（BB-IND 11411），在复发性滤泡性淋巴瘤患者中输注自体CD 19特异性T细胞（表达第一代CAR）。在这项研究中，我们提出了一项新的临床试验，将预先制备的来自脐带血（UCB）的CD 19特异性T细胞输注给异基因HSCT后复发的B系白血病/淋巴瘤患者。值得注意的是，该试验将是（i）同种异体HSCT后CD 19特异性T细胞的“首次人体”输注，（ii）首次输注表达能够提供完全能力的第二代CAR的T细胞T-细胞激活信号（通过嵌合CD 3-<$;和CD 28），和（iii）第一个通过正电子发射断层扫描（PET）在体内成像遗传修饰的T细胞的分布及其活化状态，一个放射基因治疗的例子我们假设，UCB来源的HLA不匹配的CD 19特异性T细胞克隆的同质群体的库的先验代将允许T细胞在患者群体中以安全和及时的方式输注，几乎没有存活的机会。T细胞分离、遗传修饰和扩增将遵循MDACC的标准操作规程，T细胞剂量将根据FDA对主细胞库规定的质量控制/保证标准在我们的药品生产质量管理规范（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.