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）总是致命的疾病，非常需要更好的治疗方式。白痴型（ID）是一种明确定义的肿瘤特异性抗原，我们和其他人表明，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。 已经针对MM和B细胞淋巴瘤探索了基于ID的免疫疗法，并且在大多数研究中，已经注意到增强的ID特异性免疫反应，而偶尔只能在患者中观察到临床反应。 这可能表明，增强的免疫力可能仍然太弱，无法造成严重的肿瘤破坏和/或可能产生非抗浅的免疫反应。 我们假设ID特异性CTL杀死了骨髓瘤细胞，而ID特异性T-辅助（Type-2; Th2）细胞可能会促进体内骨髓瘤细胞的生长和存活。 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消除残留的肿瘤细胞，这可以通过转移到大量的离体生成的特定特异性CTL的患者中来实现。 我们的假设将通过在骨髓瘤患者中产生和表征ID特异性T细胞，检查其在体外和体内（SCID-HU宿主）对骨髓瘤细胞的影响，并将ID特异性CTL产生至临床量表以进行收养免疫治疗。 我们将从血液中传播不同亚群的ID特异性T细胞，例如CD4+ Th1和Th2和CD8+ CTL，并检查来自肿瘤部位的T细胞，例如骨髓和患者的局灶性病变，以表现出其抗原特异性，亚群和功能。 从血液和肿瘤部位获得的ID特异性T细胞的线和克隆将在体外和骨髓瘤SCID-HU小鼠模型中的原发性骨髓瘤细胞上进行调节作用。 通过这些研究，将获得有关不同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产生患者的CTL进行过养免疫疗法。 我们将定义在体外生成此类T细胞的最佳条件，并在体内传播之前增加体内特定T细胞的数量。 当应该将同种异体ID特定的CTL用于收养转移时，这也可以应用于HLA匹配的同胞供体。 这些新颖的方法将大大有助于免疫疗法诱导或改善MM患者长期生存的能力。