CMV-SPECIFIC ANTI-TUMOR IMMUNE RESPONSE IN ASTROCYTOMAS

恶性神经胶质瘤（MG）是普遍致命的，有效的治疗是有限的正常组织的附带损害。针对肿瘤特异性抗原的免疫治疗可以更精确地靶向肿瘤细胞，我们的基于树突状细胞（DC）的疫苗靶向突变的肿瘤特异性表皮生长因子受体，在MG患者中产生了免疫学和放射学反应。发现MG，而不是周围的正常脑，作为巨细胞病毒（CMV）再活化的避难所，提供了一个无与伦比的机会，颠覆，作为肿瘤特异性抗原，高免疫原性CMV蛋白，pp 65。尽管用基于DC的疫苗靶向MG中的CMV抗原具有许多优点，但许多因素明显限制了这些患者中的抗/肿瘤免疫应答。 消除CD 25+调节性T细胞或阻断细胞毒性3的创新互补策略; 淋巴细胞抗原-4诱导的T细胞耐受性可增强这种免疫应答，但这些有效佐剂的不加选择的应用具有诱导自身免疫性脑脊髓炎的风险。为了了解MG中靶向CMV抗原的局限性和风险，我们开发了一种新的鼠星形细胞瘤细胞系，该细胞系支持鼠CMV感染，并且在同基因小鼠中具有致瘤性。我们的初步小鼠研究表明，这些肿瘤在大脑中可以靶向与RNA负载的DC。我们还表明，来自MG患者的负载有pp 65 mRNA的DC以抗原特异性方式诱导CD 4+和CDS+ T细胞产生干扰素-γ，并刺激T细胞杀死感染人CMV的恶性星形胶质细胞。有趣的是，我们还发现CMV特异性T细胞优先聚集在MG患者的肿瘤部位。我们相信，我们的鼠模型系统和互补的人类研究提出的将允许选择和翻译的最有效的策略，靶向CMV相关抗原的MG患者，没有诱导自身免疫。在这个项目中，我们将使用小鼠模型，在体外人体研究相结合，以评估的安全性，并获得更好地了解恶性胶质瘤中的CMV相关蛋白的治疗靶向参与的机制。然后将使用结果来合理设计和进行临床CMV靶向临床试验。

Malignant gliomas (MGs) are univerally fatal, and effective therapy is limited by collateral damage to normal tissue. Immunotherapy directed against tumor-specific antigens may allow neoplastic cells to be targeted more precisely, and our dendritic cell (DC)-based vaccinations targeting of a mutated tumor-specific epidermal growth factor receptor have produced immunologic and radiographic responses in patients with MGs. The discovery that MGs, but not surrounding normal brain, serve as a refuge for Cytomegalovirus (CMV) reactivation provides an unparalleled opportunity to subvert, as a tumor-specific antigen, the highly immunogenic CMV protein, pp65. Despite the numerous advantages of targeting CMV antigens in MGs with DC-based vaccines, a number of factors clearly limit ant/tumor immune responses in these patients. Innovative complementary strategies that eliminate CD25+ regulatory T cells or block cytotoxic 3; lymphocyte antigen-4-induced T cell tolerance may enhance such immune responses, but the indiscriminate application of these potent adjuvants carries the risk of inducing autoimmune encephalomyelitis. In order to understand the limitations and risks of targeting CMV antigens in MGs, we have developed a novel murine astrocytoma cell line that supports infection with murine CMV and is tumorigenic in syngeneic mice. Our preliminary murine studies demonstrate that these tumors in the brain can be targeted with RNA-loaded DCs. We have also shown that DCs from patients with MGs that are loaded with pp65mRNA, induce interferon-gamma, production from CD4+ and CDS+ T-cells in an antigen-specific manner and incite T-cells to kill malignant astrocytes infected with human CMV. Interestingly, we have also found that CMV-specific T-cells preferentially accumulate at the tumor site in patients with MGs. We believe that our murine model system and the complementary human studies proposed will allow selection and translation of the most effective strategies for targeting CMV-associated antigens in patients with MGs, without the induction of autoimmunity. In this project, we will use the murine model, in combination with in vitro human studies to evaluate the safety of, and to gain a better understanding of the mechanisms involved in the therapeutic targeting of CMV-associated proteins in malignant gliomas. The results will then be used to rationally design and conduct a clinical CMV-targeted clinical trial.