Modulation of Microglia and T Cell Interactions in Malignant Glioma

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）的特征是脑实质的弥漫性浸润、复发性生长和极差的生存预后，尽管进行了积极的手术切除、化疗和放疗。尽管有上述这些干预措施，微观肿瘤仍然存在。虽然神经胶质瘤具有免疫原性，但免疫介导的根除不会发生。肿瘤特异性细胞毒性T细胞存在于神经胶质瘤中，表明免疫系统已识别这些肿瘤。然而，我们发现细胞毒性T细胞在肿瘤微环境中是无活性的。这种损伤可以部分归因于胶质瘤产生的免疫抑制细胞因子（TGF-β，IL-10）;然而，我们的实验室已经确定了中枢神经系统（CNS）抗原呈递细胞（APC）-小胶质细胞无法提供适当的共刺激。我们的假设是免疫系统不能抑制和/或根除继发于神经胶质瘤浸润性小胶质细胞的GBM，其诱导对浸润性神经胶质瘤免疫效应（CD 8+，细胞毒性）T细胞的无反应性。在我们的II期临床试验（ACTIVATE; BB-IND-9944）中，用肽疫苗治疗的GBM患者的一年无进展生存期（PFS）为61%，与标准治疗、放射和同时使用替莫唑胺的一年PFS 26.9%相比，这是有利的。尽管我们的临床试验数据很有希望，但仍有患者在进步。我们的目标是通过调节胶质瘤浸润性小胶质细胞与效应T细胞的相互作用来提高免疫治疗的疗效。我们的第一个目的是确定胶质瘤浸润小胶质细胞对幼稚CD 8 + T细胞，活化的CD 8 + T细胞和CD 4+辅助T细胞（Th 1与Th 2）的倾斜的影响。此外，我们将跟踪胶质瘤患者T细胞的活化，因为它们从体循环进入胶质瘤微环境。这些研究将证明CNS小胶质细胞如何直接影响T细胞，并且一旦在其他肿瘤类型的肿瘤微环境中，对免疫活化和反应性也具有广泛的适用性。我们接下来将用STAT-3阻断胶质瘤浸润性小胶质细胞来调节肿瘤环境中T细胞的活化。STAT-3阻断可以诱导胶质瘤中的细胞凋亡，上调小胶质细胞上的共刺激分子，甚至在免疫抑制环境如CNS胶质瘤中逆转T细胞耐受。然后将在鼠同基因脑内治疗模型中评价减弱肽疫苗功效的STAT- 3阻断的临床前测试。通过进一步阐明免疫系统未能根除或抑制胶质瘤的机制，我们希望提高未来免疫治疗的疗效，延长胶质瘤患者的寿命和生活质量。

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is characterized by a diffuse infiltration of the brain parenchyma, recurrent growth and extremely poor prognosis for survival despite aggressive surgical resection, chemotherapy, and radiation. Despite these aforementioned interventions, microscopic tumor remains. Although gliomas are immunogenic, immune-mediated eradication does not occur. Tumor-specific cytotoxic T cells are present within gliomas indicating that the immune system has recognized these tumors. However, we have found that the cytotoxic T cells are inactive in the tumor microenvironment. This impairment can be attributed, in part, to the immunosuppressive cytokines (TGF-¿, IL-10) elaborated by gliomas; however, our laboratory has identified a failure of the central nervous system (CNS) antigen presenting cells (APC) - microglia, to provide appropriate co-stimulation. Our hypothesis is that the immune system fails to suppress and/or eradicate GBMs secondary to glioma-infiltrating microglia inducing anergy to the infiltrating glioma immunological effector (CD8+, cytotoxic) T cells. In our Phase II clinical trial (ACTIVATE; BB-IND-9944) GBM patients treated with a peptide vaccine have a one-year progression free survival (PFS) of 61%, which is favorable compared to the standard of care, radiation and concurrent temozolomide with a one year PFS of 26.9%. Despite our promising clinical trial data there are patients who still progress. The goal of our project is improve the efficacy of immunotherapy by modulating the glioma infiltrating microglia interaction with effector T cells. Our first aim is to determine the influence of glioma infiltrating microglia on naive CD8+ T cells, activated CD8+ T cells, and the skewing of CD4+ helper T cells (Th1 versus Th2). Furthermore, we will follow the activation of T cells in glioma patients as they transgress from the systemic circulation into the glioma microenvironment. These studies will demonstrate how the CNS microglia directly influence T cells and has broad applicability for immune activation and reactivity once in the tumor microenvironment for other tumor types as well. We will next modulate the activation of T cells in the tumor environment with STAT-3 blockade of the glioma infiltrating microglia. STAT-3 blockade can induce apoptosis in gliomas, up regulate the co-stimulatory molecules on the microglia and reverse T cell tolerance even in an immunosuppressive environment such as CNS gliomas. Pre-clinical testing of STAT- 3 blockade attenuating the efficacy of the peptide vaccine will then be evaluated in a murine syngeneic intracerebral treatment model. By further delineating the mechanisms underlying the failure of the immune system to eradicate or suppress gliomas, we hope to improve the efficacy of future immunotherapy, increase longevity and quality of life of glioma patients.