Idiotype-specific effector T cells in multiple myeloma

多发性骨髓瘤中的独特型特异性效应T细胞

• 批准号: 6615135
• 负责人: Qing Yi
• 金额: $ 29.24万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6615135
• 关键词: B cell lymphoma; B lymphocyte; SCID mouse; antigen presenting cell; cell differentiation; cell growth regulation; cell mediated lymphocytolysis test; clinical research; clinical trials; cytotoxic T lymphocyte; dendritic cells; disease /disorder model; enzyme linked immunosorbent assay; flow cytometry; helper T lymphocyte; human subject; human therapy evaluation; immunoregulation; in situ hybridization; multiple myeloma; neoplasm /cancer immunotherapy; neoplastic cell; neoplastic growth; polymerase chain reaction; tissue /cell culture; tissue /cell preparation; tumor antigens

Multiple myeloma (MM) is an invariably fatal disease, and there is a great need for better treatment modalities. Idiotype (id) is a well defined tumor-specific antigen, and we and others have shown that id-specific cytotoxic T lymphocytes (CTLs) can lyse myeloma cells in vitro. Id-based immunotherapies have been explored for MM and B-cell lymphoma, and in most of these studies, enhanced id-specific immune responses have been noted, whereas a clinical response could only occasionally be observed in the patients. This may suggest that the enhanced immunity may still be too weak to cause significant tumor destruction and/or a nonbeneficial immune response might have been generated. We hypothesize that id-specific CTLs kill myeloma cells, whereas id-specific T-helper (type-2; Th2) cells may promote myeloma cell growth and survival in vivo. We further hypothesize that a strong tumor-specific cytotoxic immune response established in vivo will effectively suppress or eradicate residual tumor cells, which can be achieved by transfer to patients of a substantial number of ex vivo-generated specific CTLs. Our hypotheses will be tested by generating and characterizing id-specific T cells in myeloma patients, examining their effects on myeloma cells in vitro and in vivo (SCID-hu host), and generating id-specific CTLs to clinical scale for adoptive immunotherapy. We will propagate id-specific T cells of different subsets, such as CD4+ Th1 and Th2 and CD8+ CTLs, from blood and examine T cells from tumor sites, such as bone marrow and focal lesions of patients, for their antigenic specificity, subsets, and function. Lines and clones of id-specific T cells obtained from blood and tumor sites will be tested for their regulatory role on primary myeloma cells in vitro and in the myeloma SCID-hu mouse model. Through these studies, direct evidence will be obtained on whether the different id-specific T cells are able to suppress or promote the growth and survival of primary myeloma cells. This knowledge will be further used to generate CTLs from patients for adoptive immunotherapy. We will define the optimum condition for generating such T cells in vitro and immunize patients to increase the number of specific T cells in vivo before ex vivo propagation. This may also be applied to HLA-matched sibling donors when allogeneic id-specific CTLs should be used for adoptive transfer. These novel approaches will substantially contribute to the ability of immunotherapy to induce or improve long-term survival in patients with MM.

多发性骨髓瘤（MM）是一种致命的疾病，非常需要更好的治疗方式。独特型（id）是一种明确定义的肿瘤特异性抗原，我们和其他人已经证明id特异性细胞毒性T淋巴细胞（CTL）可以在体外裂解骨髓瘤细胞。 基于 id 的免疫疗法已经被探索用于 MM 和 B 细胞淋巴瘤，并且在大多数这些研究中，已经注意到增强的 id 特异性免疫反应，而临床反应只能偶尔在患者中观察到。 这可能表明增强的免疫力可能仍然太弱而不足以导致显着的肿瘤破坏和/或可能已经产生了无益的免疫反应。 我们假设 id 特异性 CTL 杀死骨髓瘤细胞，而 id 特异性 T 辅助细胞（2 型；Th2）细胞可能促进体内骨髓瘤细胞生长和存活。 我们进一步假设体内建立的强肿瘤特异性细胞毒性免疫反应将有效抑制或根除残留的肿瘤细胞，这可以通过将大量体外产生的特异性CTL转移到患者体内来实现。 我们的假设将通过在骨髓瘤患者中生成和表征 id 特异性 T 细胞、检查它们在体外和体内（SCID-hu 宿主）对骨髓瘤细胞的影响以及生成用于过继免疫治疗的临床规模的 id 特异性 CTL 来进行测试。 我们将从血液中繁殖不同亚群的 id 特异性 T 细胞，例如 CD4+ Th1 和 Th2 以及 CD8+ CTL，并检查肿瘤部位（例如患者的骨髓和局灶性病变）的 T 细胞的抗原特异性、亚群和功能。 从血液和肿瘤部位获得的 id 特异性 T 细胞系和克隆将在体外和骨髓瘤 SCID-hu 小鼠模型中测试其对原发性骨髓瘤细胞的调节作用。 通过这些研究，将获得不同id特异性T细胞是否能够抑制或促进原发性骨髓瘤细胞的生长和存活的直接证据。 这些知识将进一步用于从患者身上生成 CTL，用于过继免疫治疗。 我们将确定在体外生成此类 T 细胞的最佳条件，并对患者进行免疫，以在离体繁殖之前增加体内特定 T 细胞的数量。 当应使用同种异体 id 特异性 CTL 进行过继转移时，这也可能适用于 HLA 匹配的兄弟姐妹供体。 这些新方法将极大地提高免疫疗法诱导或改善 MM 患者长期生存的能力。