Inhibition of STAT-3 to stimulate immune function for GBM

描述(由申请人提供)：我们最近在新诊断的多形性胶质母细胞瘤(GBM)患者中展示了针对EGFRvIII的多肽疫苗在II期临床试验中的显著临床疗效。尽管进展的时间有了令人印象深刻的延迟，存活率提高了100%，但这些患者仍然死于他们的疾病。通过直接研究GBM患者的免疫反应，包括肿瘤微环境，我们发现了深刻的免疫抑制因素，包括诱导T细胞无能的Tregs、免疫抑制细胞因子和小胶质细胞。这表明，即使在遇到肿瘤微环境时对抗原靶点产生了强烈的系统免疫反应，这些反应也会在功能上变得惰性。许多患者无法接受肿瘤摘除，并患有实体癌。目前可用的免疫激活剂不足以克服这种免疫耐受和免疫抑制。然而，一种新的STAT-3小分子抑制剂在实体癌症患者中显示出显著的免疫激活特性，并可用于有效地与癌症患者的免疫治疗协同作用。多形性胶质母细胞瘤是一种常见的致命脑瘤，尽管有新的治疗策略的发展，但其存活率仍然很低，只有14个月。我们已经证明，免疫疗法是一种很有前途的治疗方式，可以使疾病最小的患者的中位生存期增加一倍。这种方法只在巨型癌症患者中取得最小的成功，因此需要WP1066等化合物来克服肿瘤介导的这种深刻的免疫抑制，并进一步增强免疫反应。

DESCRIPTION (provided by applicant): We have recently demonstrated marked clinical efficacy in a phase II clinical trial with a peptide vaccine targeting EGFRvIII in newly diagnosed glioblastoma multiforme (GBM) patients. Despite an impressive delay in time to progression and 100% increase in survival, these patients nonetheless still succumb to their disease. By studying directly the immune response with GBM patients, including the tumor microenvironment, we have identified profound immunological suppressive factors including Tregs, immunosuppressive cytokines, and microglia that induce T cell anergy. This indicates that even if a vigorous systemic immune response was generated to an antigen target upon encountering the tumor microenvironment these responses would be rendered functionally inert. Many patients are not able to undergo a tumor debulking and have solid cancers. Currently available immune activators are insufficient to overcome this immune tolerance and immunosuppression. However, a novel small molecular inhibitor of STAT-3 has demonstrated marked immune activation properties in this setting of patients with solid cancers and could be employed to potently synergize with immunotherapies for patients with cancer. Glioblastoma multiforme is a common and deadly brain tumor that despite the development of new therapeutic strategies, survival remains at a dismal 14 months. We have shown that immunotherapy is a promising treatment modality that can double the median survival in patients with minimal disease. This approach is only minimally successful in patients with bulky cancers and thus compounds such as WP1066 are needed to overcome this profound immunosuppression mediated by the tumor and further enhance immunological responses.