Immunotherapy with Gamma Delta T Cells for B Cell Tumors

使用 Gamma Delta T 细胞治疗 B 细胞肿瘤的免疫疗法

• 批准号: 7452501
• 负责人: CRAIG T MORITA
• 金额: $ 22.1万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7452501
• 关键词: Adjuvant; Adult; Antigens; B lymphoid malignancy; B-Cell Lymphomas; B-Cell Neoplasm; B-Lymphocytes; Cell Line; Cell physiology; Cells; Disease; Growth; Growth Factor; Human; Immunity; Immunotherapy; In Vitro; Interleukin-2; Knowledge; Lead; Ligands; Lymphoma; Malignant - descriptor; Malignant lymphoid neoplasm; Memory; Molecular; Monkeys; Multiple Myeloma; Non-Hodgkin' s Lymphoma; Partial Remission; Patients; Proliferating; Property; Protocols documentation; Role; SCID Beige Mouse; SCID Mice; Stable Disease; T memory cell; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Vaccination; Vaccine Adjuvant; Vaccines; Zoledronate; base; bisphosphonate; cytokine; in vivo; indolepropanol phosphate; killings; microbial; mouse model; response

DESCRIPTION (provided by applicant): Gammadelta T cells represent a unique subset of T cells that bridge innate and adaptive immunity by recognizing self and foreign nonpeptide antigens. In addition to their role in microbial immunity, there is strong evidence that human gammadelta T cells help regulate B cell malignancies such as non-Hodgkin's lymphoma (NHL) and multiple myeloma. Supporting this hypothesis, gammadelta? T cells expand in some patients with lymphoid malignancies to up to 42% of circulating T cells. Human Vgamma2Vdelta2 T cells recognize and kill a subset of NHLs and multiple myelomas. Vgamma2Vdelta2 T cells can provide immunity for NHL in a SCID mouse model. Moreover, immunotherapy of lymphoma patients with synthetic bisphosphonate antigens and IL-2 to stimulate Vgamma2Vdelta2 T cells shows promise since it resulted in partial remissions or stable disease in 4 of 5 patients that had Vgamma2Vdelta2 T cell proliferation. For this immunotherapy to be more effective, basic knowledge is needed about how Vgamma2Vdelta2 T cells respond to nonpeptide antigens, how gammadelta T cell memory develops, and what are the most effective ways to stimulate Vgamma2Vdelta2 T cells in vivo. We have found that adult Vgamma2Vdelta2 T cells are almost exclusively memory cells that are divided into 3 subsets, central memory, effector memory, and effector CD45RA+memory. Each subset has distinctive functional and migratory properties. We find that central memory Vgamma2Vdelta2 T cells are deleted or anergized in multiple myeloma patients that have been treated with the bisphosphonate, zolendronate, in the absence of rIL-2. Here we propose to test the hypothesis that Vgamma2Vdelta2 T cells recognize and kill a subset of malignant B cells that have elevated levels of IPP and NKG2D ligands. Activating V?2V?2 T cells with nonpeptide antigens and growth factors can lead to the elimination or stabilization of disease in patients with B cell malignancies. In Aim 1, we will correlate expression of NKG2D ligands with the ability of malignant B cells to stimulate Vgamma2Vdelta2 T cells. In Aim 2, we will test different memory subsets of Vgamma2Vdelta2 T cells for their ability to control lymphomas in adaptive immunotherapy in an in vivo SCID-beige mouse model. In Aim 3, we will test vaccination protocols using bisphosphonate antigens, adjuvants, and growth cytokines in monkeys for their ability to stimulate Vgamma2Vdelta2 T cells. These studies will help to elucidate the molecular basis of Vgamma2Vdelta2T cell recognition of malignant B cells and the function of memory gammadelta T cell subsets in lymphoma immunity and will provide crucial information on optimising immunotherapy with gammadelta T cells.

描述（由申请人提供）：Gammadelta T 细胞代表 T 细胞的独特子集，其通过识别自身和外来非肽抗原来桥接先天免疫和适应性免疫。除了在微生物免疫中的作用外，有强有力的证据表明，人类 γδ T 细胞有助于调节 B 细胞恶性肿瘤，例如非霍奇金淋巴瘤 (NHL) 和多发性骨髓瘤。支持这个假设，gammadelta？在一些淋巴恶性肿瘤患者中，T 细胞扩增至循环 T 细胞的 42%。人类 Vgamma2Vdelta2 T 细胞识别并杀死 NHL 和多发性骨髓瘤的子集。 Vgamma2Vdelta2 T 细胞可以在 SCID 小鼠模型中提供 NHL 免疫力。此外，用合成双膦酸盐抗原和 IL-2 刺激 Vgamma2Vdelta2 T 细胞对淋巴瘤患者进行免疫治疗显示出前景，因为它使 5 名具有 Vgamma2Vdelta2 T 细胞增殖的患者中有 4 名部分缓解或病情稳定。为了使这种免疫疗法更加有效，需要了解 Vgamma2Vdelta2 T 细胞如何响应非肽抗原、gammadelta T 细胞记忆如何发展以及体内刺激 Vgamma2Vdelta2 T 细胞的最有效方法是什么等基础知识。 我们发现成人Vgamma2Vdelta2 T细胞几乎都是记忆细胞，分为3个亚群：中央记忆、效应记忆和效应CD45RA+记忆。每个子集都具有独特的功能和迁移特性。我们发现，在缺乏 rIL-2 的情况下，接受双膦酸盐、唑来膦酸盐治疗的多发性骨髓瘤患者中，中央记忆 Vgamma2Vdelta2 T 细胞被删除或失去活力。在这里，我们建议检验以下假设：Vgamma2Vdelta2 T 细胞识别并杀死 IPP 和 NKG2D 配体水平升高的恶性 B 细胞子集。用非肽抗原和生长因子激活 V?2V?2 T 细胞可以消除或稳定 B 细胞恶性肿瘤患者的疾病。在目标 1 中，我们将 NKG2D 配体的表达与恶性 B 细胞刺激 Vgamma2Vdelta2 T 细胞的能力相关联。在目标 2 中，我们将在体内 SCID 米色小鼠模型中测试 Vgamma2Vdelta2 T 细胞的不同记忆子集在适应性免疫治疗中控制淋巴瘤的能力。在目标 3 中，我们将使用双磷酸盐抗原、佐剂和生长细胞因子在猴子中测试疫苗接种方案，以确定其刺激 Vgamma2Vdelta2 T 细胞的能力。这些研究将有助于阐明Vgamma2Vdelta2T细胞识别恶性B细胞的分子基础以及记忆gammadelta T细胞亚群在淋巴瘤免疫中的功能，并将为优化gammadelta T细胞免疫治疗提供重要信息。