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)的特点是弥漫性脑实质浸润，复发生长和极差的生存预后，尽管积极的手术切除，化疗和放疗。尽管采取了上述干预措施，但显微肿瘤仍然存在。虽然胶质瘤是免疫原性的，但免疫介导的根除不会发生。胶质瘤中存在肿瘤特异性细胞毒性T细胞，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不活跃的。这种损害可以部分归因于胶质瘤所阐述的免疫抑制细胞因子(转化生长因子-β，IL-10)；然而，我们的实验室发现，中枢神经系统(CNS)抗原提呈细胞(APC)-小胶质细胞未能提供适当的共同刺激。我们的假设是，免疫系统不能抑制和/或消除继发于胶质瘤浸润性小胶质细胞的GBM，导致对浸润性胶质瘤免疫效应T细胞(CD8+，细胞毒)无反应。在我们的第二阶段临床试验(ACTIVATE；BB-IND-9944)中，接受多肽疫苗治疗的GBM患者的一年无进展存活率(PFS)为61%，这比接受治疗、放疗和同时接受替莫唑胺治疗的标准患者的一年无进展存活率(PFS)26.9%要好。尽管我们的临床试验数据前景看好，但仍有患者在进步。本课题的目标是通过调节胶质瘤浸润性小胶质细胞与效应性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侵袭小胶质细胞对初始CD8+T细胞、激活的CD8+T细胞以及CD4+辅助T细胞(Th1和Th2)的偏斜的影响。此外，我们将跟踪胶质瘤患者T细胞从体循环进入胶质瘤微环境时的激活情况。这些研究将展示中枢神经系统小胶质细胞如何直接影响T细胞，并具有广泛的适用性，一旦在肿瘤微环境中对其他类型的肿瘤也具有免疫激活和反应。接下来，我们将通过STAT-3阻断胶质瘤浸润性小胶质细胞来调节肿瘤环境中T细胞的激活。STAT-3阻断可以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，甚至在中枢神经系统胶质瘤等免疫抑制环境中也是如此。随后将在小鼠同基因脑内治疗模型中评估STAT-3阻断减弱多肽疫苗效果的临床前测试。通过进一步阐明免疫系统无法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，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.