Genetic Targeting of T cells to B cell malignancies

T 细胞针对 B 细胞恶性肿瘤的遗传靶向

基本信息

批准号：
6951500
负责人：
Renier Joseph Brentjens
金额：
$ 13.44万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2007-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): CD19 is selectively expressed on most B cell malignancies and normal B cells but not on blood stem cells and is therefore an attractive target for cancer immunotherapy. A retroviral vector encoding a CD19 specific single chain fragment (scFv) antibody fused to a TCR zeta chain has been developed. T cells transduced to express this artificial T cell receptor (termed 19z1) specifically lyse human CD19 (hCD19) expressing tumor cell lines in vitro. Furthermore, treatment of SCID-Beige mice bearing established systemic hCD19+ Raji tumor cells with 19z1 modified human T cells results in an increased time to tumor progression and overall survival in a dose dependent manner when compared to mice treated with T cells transduced with an irrelevant artificial T cell receptor (Pz1). However, interpretation of this data is limited by the xenogeneic nature of the T cells and tumor cells to the SCID-Beige mouse, as well as the immune-compromised state of the host. Therefore, the overall objective of this proposal is to better define the activity of the 19z1 transduced T cells using a syngeneic immune competent mouse model. To this end, specific aim #1 of this proposal will establish a tumor model of syngeneic EL4(hCD19) tumor cells in an immune competent hCD19 transgenic mouse and establish whether 19z1+ murine T cells are able to eradicate disease in this model. To test the hypothesis that T helper cells play an important role in adoptive T cell therapy, aim #2 will define the role of transduced CD4+ T cells in the cytotoxic activity, homing and proliferation of transduced CD8+ T cells. Specific aim #3 will test the hypothesis that secondary lymphoid tissues and bone marrow in cured mice will maintain a persistent population of transduced T cells. The functional status of these T cells will be analyzed by rechallenge of cured mice with EL4(hCD19) tumor cells. The data derived from these studies will be applied to the rational development of future clinical trials in human subjects with B cell malignancies.

描述（由申请人提供）：CD19 在大多数 B 细胞恶性肿瘤和正常 B 细胞上选择性表达，但在血液干细胞上不表达，因此是癌症免疫治疗的一个有吸引力的靶标。编码与 TCR zeta 链融合的 CD19 特异性单链片段 (scFv) 抗体的逆转录病毒载体已开发出来。转导表达这种人工 T 细胞受体（称为 19z1）的 T 细胞在体外特异性裂解表达人 CD19 (hCD19) 的肿瘤细胞系。此外，与用不相关的人工转导的 T 细胞治疗的小鼠相比，用 19z1 修饰的人 T 细胞治疗携带已建立的系统性 hCD19+ Raji 肿瘤细胞的 SCID-Beige 小鼠，会以剂量依赖的方式延长肿瘤进展时间和总体存活率。 T 细胞受体 (Pz1)。然而，对该数据的解释受到 SCID-Beige 小鼠 T 细胞和肿瘤细胞的异种性质以及宿主的免疫受损状态的限制。因此，该提案的总体目标是使用同基因免疫小鼠模型更好地定义 19z1 转导 T 细胞的活性。为此，该提案的具体目标#1将在具有免疫能力的hCD19转基因小鼠中建立同基因EL4(hCD19)肿瘤细胞的肿瘤模型，并确定19z1+小鼠T细胞是否能够根除该模型中的疾病。为了检验 T 辅助细胞在过继性 T 细胞治疗中发挥重要作用的假设，目标 #2 将定义转导的 CD4+ T 细胞在转导的 CD8+ T 细胞的细胞毒活性、归巢和增殖中的作用。具体目标#3 将检验以下假设：治愈小鼠的次级淋巴组织和骨髓将维持持续的转导 T 细胞群。将通过用 EL4(hCD19) 肿瘤细胞重新攻击治愈的小鼠来分析这些 T 细胞的功能状态。从这些研究中获得的数据将应用于未来针对 B 细胞恶性肿瘤人类受试者的临床试验的合理开发。