Vaccine-Dac/Bev Combinatorial Therapy in Ovarian Cancer

卵巢癌疫苗-Dac/Bev 联合治疗

• 批准号: 8189152
• 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/8189152
• 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. PUBLIC HEALTH RELEVANCE: We propose a phase I/II clinical study to test combination immunotherapy with a vaccine that comprises all possible tumor antigens plus antiangiogenesis and immunomodulation therapy blocking regulatory T cells. Our hypothesis is that cancer vaccines require rational combinations that target and change the tumor microenvironment to achieve clinical efficacy. If successful, we will significantly aid the cancer immunotherapy field by enabling many tumor vaccines to acquire activity.

描述（由申请人提供）：卵巢癌是女性中第五常见的癌症。越来越多的证据表明，卵巢癌是适合免疫治疗。我们的工作表明，肿瘤浸润效应T细胞预测改善的结果，而肿瘤浸润Treg预测卵巢癌患者的生存期较短。然而，迄今为止，癌症疫苗产生了适度的结果。我们实验室和我们合作者的工作表明，肿瘤微环境中的两个重要屏障阻止了抗肿瘤效应T细胞的植入，扩增和功能; a）肿瘤中的血管内皮建立了血液-肿瘤屏障，防止效应T细胞外渗到肿瘤中（通过下调细胞粘附分子），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的表达）也诱导肿瘤中CCR 10 + Treg细胞的积累，而Treg反过来表达高水平的VEGF。因此，尽管VEGF阻断可以减弱血液-肿瘤屏障，但它也可以在肿瘤微环境中产生Treg积累的反弹增加，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，从而使癌症疫苗诱导的相对较弱的抗肿瘤免疫应答变得临床有效。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我们的假设;在最近完成的试点研究中，我们观察到33%的客观放射学反应和66%的临床受益率在卵巢癌患者接受弱疫苗（不成熟的DC脉冲与肿瘤裂解物上清液）结合VEGF阻断和节拍环磷酰胺。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这一假设，即通过VEGF阻断结合Treg耗竭重新编辑肿瘤微环境，使肿瘤疫苗能够达到临床疗效。目的1）进行自体全肿瘤抗原致敏的树突状细胞疫苗与使用地尼白介素diftitox（Ontak）和抗VEGF抗体（Bevacizumab）的Treg去除的合理组合的初步临床试验。目的2）评价疫苗和联合免疫治疗的安全性、可行性和临床效果。目的3）评估疫苗和联合免疫治疗在外周和肿瘤微环境中的免疫效果。 公共卫生相关性：我们提出了一项I/II期临床研究，以测试联合免疫疗法与疫苗，包括所有可能的肿瘤抗原加上抗血管生成和免疫调节治疗阻断调节性T细胞。我们的假设是，癌症疫苗需要合理的组合，靶向和改变肿瘤微环境，以达到临床疗效。如果成功，我们将通过使许多肿瘤疫苗获得活性来显著帮助癌症免疫治疗领域。