Vaccine-Dac/Bev Combinatorial Therapy in Ovarian Cancer

卵巢癌疫苗-Dac/Bev 联合治疗

• 批准号: 8294558
• 负责人: GEORGE COUKOS
• 金额: $ 34.8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294558
• 关键词: Antibodies; Apoptosis; Area; Attenuated; Autoimmune Process; Autologous; Blood; Cancer Patient; Cancer Vaccines; Carcinoma; Cell Adhesion; Cell Adhesion Molecules; Cells; Clinical; Clinical Research; Clinical Trials; Combined Vaccines; Cyclophosphamide; Data; Dendritic Cell Vaccine; Denileukin Diftitox; Disease; Down-Regulation; Endothelin B Receptor; Endothelium; Engraftment; Ensure; Extravasation; GPR2 gene; Homing; Human Experimentation; Hypoxia; IL2RA gene; Immune; Immune response; Immunity; Immunotherapy; Intercellular adhesion molecule 1; Investigation; Laboratories; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Modeling; Mus; Necrosis; Outcome; Ovarian; Patients; Pharmaceutical Preparations; Phase; Physiologic pulse; Pilot Projects; Play; Population; Regulatory T-Lymphocyte; Role; Safety; Solid Neoplasm; Suppressor-Effector T-Lymphocytes; Systemic Therapy; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Tumor Antigens; Tumor Escape; Tumor Necrosis Factor Ligand Superfamily Member 6; Tumor-Derived; Up-Regulation; Vaccine Therapy; Vaccines; Vascular Endothelial Growth Factors; Vascular Endothelium; Woman; Work; angiogenesis; antiangiogenesis therapy; arm; bevacizumab; cancer immunotherapy; chemokine; clinical effect; clinical efficacy; combinatorial; immunogenic; immunoregulation; improved; killings; neoplastic cell; prevent; randomized trial; response; synergism; tumor; tumor growth

DESCRIPTION (provided by applicant): Ovarian cancer is the 5th most common cancer in women. Mounting evidence indicates that ovarian cancer is amenable to immune therapy. Our work has shown that tumor-infiltrating effector T cells predict improved outcome, while tumor-infiltrating Treg predict shorter survival in patients with ovarian cancer. However, cancer vaccines have produced modest results to date. Work from our lab and our collaborators has shown that two important barriers in the tumor microenvironment prevent the engraftment, expansion and function of antitumor effector T cells; a) vascular endothelium in tumors erects a blood-tumor barrier preventing extravasation of effector T cells into tumors (through down-regulation of cell adhesion molecules), or killing extravasating T cells in tumors (through FasL-mediated apoptosis); b) Treg cells located in the tumor microenvironment suppress the function of effector T cells. Importantly, we recently found that these two mechanisms are interconnected; hypoxia (which drives expression of VEGF) induces also accumulation of CCR10+ Treg cells in tumors, while Treg in turn express high levels of VEGF. Thus, although VEGF blockade can attenuate the blood-tumor barrier it can also produce a rebound increase in Treg accumulation in the tumor microenvironment, preserving tolerance. In this case, suppression of Treg could deprive tumors from a critical homeostatic tolerance mechanism and could produce a powerful immunomodulatory synergism at the tumor microenvironment, allowing a relatively weak antitumor immune response induced by cancer vaccine to become clinically effective. We hypothesize that combined neutralization of VEGF and Treg can produce powerful immunomodulatory interactions to greatly enhance the efficacy of vaccine therapy. Preliminary clinical experimental data lend support to our hypothesis; in a recently completed pilot study we observed a 33% objective radiographic response and 66% clinical benefit rate in ovarian cancer patients receiving a weak vaccine (immature DCs pulsed with tumor lysate supernatants) combined with VEGF blockade and metronomic cyclophosphamide. Here we propose a phase I/II clinical study that will enable us to start carefully testing the hypothesis that re-editing the tumor microenvironment through VEGF blockade combined with Treg depletion allows tumor vaccines to achieve clinical efficacy. The following Aims are proposed: Aim 1) Conduct a pilot clinical trial of autologous whole tumor antigen-pulsed dendritic cell vaccine combined rationally with Treg depletion using denileukin diftitox (Ontak) and anti-VEGF antibody (Bevacizumab). Aim 2) Assess the safety, feasibility and clinical effects of vaccine and combinatorial immunotherapy. Aim 3) Assess the immune effects of vaccine and combinatorial immunotherapy in the periphery and at the tumor microenvironment.

描述（由申请人提供）：卵巢癌是女性第五大常见癌症。越来越多的证据表明卵巢癌适合免疫治疗。我们的工作表明，肿瘤浸润效应 T 细胞可预测卵巢癌患者预后的改善，而肿瘤浸润 Treg 则可预测较短的生存期。然而，迄今为止，癌症疫苗只取得了有限的成果。我们实验室和合作者的工作表明，肿瘤微环境中的两个重要障碍阻碍了抗肿瘤效应 T 细胞的植入、扩增和功能； a) 肿瘤中的血管内皮建立血肿瘤屏障，防止效应 T 细胞外渗到肿瘤中（通过细胞粘附分子的下调），或杀死肿瘤中外渗的 T 细胞（通过 FasL 介导的细胞凋亡）； b) 位于肿瘤微环境中的Treg细胞抑制效应T细胞的功能。重要的是，我们最近发现这两种机制是相互关联的。缺氧（驱动 VEGF 表达）还会诱导肿瘤中 CCR10+ Treg 细胞的积累，而 Treg 反过来又表达高水平的 VEGF。因此，虽然 VEGF 阻断可以减弱血肿瘤屏障，但它也可以使肿瘤微环境中 Treg 积累反弹增加，从而保持耐受性。在这种情况下，抑制Treg可以使肿瘤失去关键的稳态耐受机制，并可以在肿瘤微环境中产生强大的免疫调节协同作用，使癌症疫苗诱导的相对较弱的抗肿瘤免疫反应变得临床有效。我们假设 VEGF 和 Treg 的联合中和可以产生强大的免疫调节相互作用，从而大大增强疫苗治疗的功效。初步的临床实验数据支持了我们的假设；在最近完成的一项试点研究中，我们观察到接受弱疫苗（用肿瘤裂解物上清液脉冲的未成熟 DC）结合 VEGF 阻断和节律环磷酰胺的卵巢癌患者的客观放射学反应为 33%，临床受益率为 66%。在这里，我们提出了一项 I/II 期临床研究，这将使我们能够开始仔细测试以下假设：通过 VEGF 阻断结合 Treg 耗竭来重新编辑肿瘤微环境，使肿瘤疫苗能够实现临床疗效。提出以下目标： 目标 1) 使用地尼白蛋白 diftitox (Ontak) 和抗 VEGF 抗体 (Bevacizumab) 合理结合 Treg 耗竭的自体全肿瘤抗原脉冲树突状细胞疫苗进行试点临床试验。目标2）评估疫苗和组合免疫疗法的安全性、可行性和临床效果。目标 3) 评估疫苗和组合免疫疗法在外周和肿瘤微环境中的免疫效果。