Inhibition of STAT-3 to stimulate immune function for GBM

抑制 STAT-3 刺激 GBM 免疫功能

• 批准号: 7394119
• 负责人: RAYMOND J BUDDE
• 金额: $ 14.7万
• 依托单位: HOUSTON PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394119
• 关键词: Adjuvant; Antigen Targeting; Antigen-Presenting Cells; Brain Neoplasms; CD80 gene; CD8B1 gene; Cancer Patient; Clinical Trials; Development; Disease; Dose; Enhancing Antibodies; Excision; Glioblastoma; Guanosine Monophosphate; IL2RA gene; Immune; Immune Tolerance; Immune response; Immunologic Adjuvants; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Malignant Glioma; Malignant Neoplasms; Manufacturer Name; Mediating; Microglia; Microscopic; Modality; Modeling; Molecular; Mus; Neuraxis; Newly Diagnosed; Numbers; Patients; Penetration; Peptide Vaccines; Phase; Phase II Clinical Trials; Phosphorylation; Preparation; Production; Property; Range; Research; Residual Tumors; Secondary to; Solid; Solid Neoplasm; T-Cell Activation; T-Lymphocyte; Therapeutic immunosuppression; Time; Toxic effect; Tumor Burden; Tumor Debulking; Vaccinated; Vaccine Clinical Trial; ZAP-70 Gene; anergy; clinical efficacy; cytokine; cytotoxic; design; epidermal growth factor receptor VIII; essays; immune function; in vivo; inhibitor/antagonist; monocyte; novel; novel therapeutics; response; tumor

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.

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针对EGFRvIII的肽疫苗对新诊断的多形性胶质母细胞瘤（GBM）患者的显著临床疗效。尽管进展时间明显延迟，生存率提高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，我们发现了深层次的免疫抑制因子，包括Tregs、免疫抑制细胞因子和诱导T细胞能量的小胶质细胞。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全身免疫反应，这些反应也会在功能上变得惰性。许多患者不能进行肿瘤减容手术，患上了实体癌。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患者中显示出显著的免疫激活特性，可以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，尽管发展了新的治疗策略，但其生存期仍然只有令人沮丧的14个月。我们已经证明免疫疗法是一种很有希望的治疗方式，可以使最小疾病患者的中位生存期增加一倍。这种方法仅在体积较大的癌症患者中成功，因此需要诸如WP1066之类的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。