Modulation of Microglia and T Cell Interactions in Malignant Glioma

描述（申请人提供）：多形性胶质母细胞瘤（GBM）的特点是脑实质弥漫性浸润，复发性生长，尽管积极的手术切除，化疗和放疗，生存预后极差。尽管有上述的干预措施，显微肿瘤仍然存在。虽然胶质瘤是免疫原性的，但免疫介导的根除并不发生。肿瘤特异性细胞毒性T细胞存在于胶质瘤中，表明免疫系统已经识别了这些肿瘤。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。这种损伤部分归因于神经胶质瘤产生的免疫抑制细胞因子（TGF-¿，IL-10）；然而，我们的实验室已经发现中枢神经系统（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无法抑制和/或根除胶质瘤浸润性小胶质细胞继发的GBMs，从而诱导浸润性胶质瘤免疫效应（CD8+，细胞毒性）T细胞的能量。在我们的II期临床试验（ACTIVATE; db - ind -9944）中，接受肽疫苗治疗的GBM患者的一年无进展生存期（PFS）为61%，与标准护理、放疗和同时使用替莫唑胺的一年PFS为26.9%相比，这是有利的。尽管我们的临床试验数据很有前景，但仍有患者病情恶化。我们项目的目标是通过调节胶质瘤浸润小胶质细胞与效应T细胞的相互作用来提高免疫治疗的疗效。我们的第一个目标是确定胶质瘤浸润小胶质细胞对幼稚CD8+ T细胞、活化CD8+ T细胞和CD4+辅助性T细胞（Th1 vs Th2）偏态的影响。此外，我们将跟踪胶质瘤患者体内T细胞从体循环进入胶质瘤微环境时的活化情况。这些研究将证明中枢神经系统小胶质细胞如何直接影响T细胞，并且在其他肿瘤类型的肿瘤微环境中也具有广泛的免疫激活和反应性适用性。接下来，我们将通过STAT-3阻断胶质瘤浸润小胶质细胞来调节肿瘤环境中T细胞的激活。即使在免疫抑制环境如中枢神经胶质瘤中，STAT-3阻断也能诱导胶质瘤细胞凋亡，上调小胶质细胞上的共刺激分子，逆转T细胞耐受。临床前测试STAT- 3阻断剂减毒肽疫苗的功效，然后将在小鼠同源脑内治疗模型中进行评估。通过进一步描述免疫系统根除或抑制胶质瘤失败的机制，我们希望提高未来免疫治疗的疗效，增加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.