Immunotherapy with Gamma Delta T Cells for B Cell Tumors

描述（由申请人提供）：γ δ T细胞代表一种独特的T细胞亚群，通过识别自身和外源非肽抗原来连接先天性免疫和适应性免疫。除了它们在微生物免疫中的作用之外，有强有力的证据表明人类γ δ 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。支持这一假设的，伽玛德尔塔？在一些淋巴恶性肿瘤患者中，T细胞扩增至高达循环T细胞的42%。人V γ 2 Vdelta 2 T细胞识别并杀死NHL和多发性骨髓瘤的子集。V γ 2 V δ 2 T细胞可以在SCID小鼠模型中提供对NHL的免疫。此外，用合成的双膦酸盐抗原和IL-2刺激V γ 2 V δ 2 T细胞的淋巴瘤患者的免疫疗法显示出希望，因为它在具有V γ 2 V δ 2 T细胞增殖的5名患者中的4名中导致部分缓解或稳定的疾病。为了使这种免疫疗法更有效，需要了解Vgamma 2 Vdelta 2 T细胞如何对非肽抗原做出反应，γ δ T细胞记忆如何发展，以及体内刺激Vgamma 2 Vdelta 2 T细胞的最有效方法是什么。 我们已经发现，成人V γ 2 V δ 2 T细胞几乎完全是记忆细胞，分为3个亚群，中央记忆，效应记忆和效应CD 45 RA+记忆。每个子集具有独特的功能和迁移特性。我们发现，在rIL-2不存在的情况下，用双膦酸盐（唑来膦酸盐）治疗的多发性骨髓瘤患者的中央记忆性V γ 2 V δ 2 T细胞被删除或无反应。在这里，我们提出测试的假设，V γ 2 V δ 2 T细胞识别和杀死恶性B细胞的一个子集，具有升高水平的IPP和NKG 2D配体。启动V星？2V？2非肽抗原和生长因子的T细胞可导致B细胞恶性肿瘤患者疾病的消除或稳定。在目的1中，我们将NKG 2D配体的表达与恶性B细胞刺激V γ 2 V δ 2 T细胞的能力相关联。在目标2中，我们将在体内SCID-beige小鼠模型中测试Vgamma 2 Vdelta 2 T细胞的不同记忆亚群在适应性免疫疗法中控制淋巴瘤的能力。在目标3中，我们将在猴中测试使用双膦酸盐抗原、佐剂和生长细胞因子的疫苗接种方案刺激V γ 2 Vdelta 2 T细胞的能力。这些研究将有助于阐明恶性B细胞的Vgamma 2 Vdelta 2 T细胞识别的分子基础和记忆性γ δ T细胞亚群在淋巴瘤免疫中的功能，并将提供优化γ δ T细胞免疫治疗的关键信息。

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.