Inhibition of STAT-3 to stimulate immune function for GBM

描述（由申请人提供）：我们最近在一项II期临床试验中证明了靶向EGFRvIII的肽疫苗在新诊断的多形性胶质母细胞瘤（GBM）患者中的显著临床疗效。尽管进展时间延迟令人印象深刻，生存率增加100%，但这些患者仍然死于疾病。通过直接研究GBM患者的免疫应答，包括肿瘤微环境，我们已经确定了深刻的免疫抑制因子，包括TcR，免疫抑制细胞因子和诱导T细胞无能的小胶质细胞。这表明，即使在遇到肿瘤微环境时对抗原靶标产生了强烈的全身免疫应答，这些应答也将在功能上呈惰性。许多患者不能进行肿瘤减积而患有实体癌。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，一种新型的STAT-3小分子抑制剂在实体癌患者中表现出显著的免疫激活特性，可用于与癌症患者的免疫疗法有效协同。多形性胶质母细胞瘤是一种常见且致命的脑肿瘤，尽管开发了新的治疗策略，但生存期仍然只有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，可以使轻微疾病患者的中位生存期增加一倍。这种方法在患有大体积癌症的患者中仅获得最低限度的成功，因此需要诸如WP 1066的化合物来克服这种由肿瘤介导的深刻的免疫抑制并进一步增强免疫应答。

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.