Vaccine-Dac/Bev Combinatorial Therapy in Ovarian Cancer

简介(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，卵巢癌可以接受免疫治疗。我们的工作表明，肿瘤浸润性效应T细胞预测卵巢癌患者的预后改善，而肿瘤浸润性Treg细胞预测卵巢癌患者较短的生存期。然而，到目前为止，癌症疫苗产生的效果不大。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屏障可阻止抗肿瘤效应T细胞的植入、扩增和功能：a)肿瘤中的血管内皮细胞建立血-肿瘤屏障，阻止效应T细胞渗入肿瘤(通过下调细胞黏附分子)，或杀死肿瘤中渗出的T细胞(通过FasL介导的凋亡)；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(驱动血管内皮生长因子的表达)也会诱导肿瘤中CCR10+Treg细胞的聚集，而Treg反过来又表达高水平的血管内皮生长因子。因此，尽管阻断血管内皮生长因子可以减弱血-肿瘤屏障，但它也可以产生肿瘤微环境中Treg积聚的反弹增加，从而保持耐受性。在这种情况下，抑制Treg可以剥夺肿瘤关键的动态平衡耐受机制，并可以在肿瘤微环境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在临床上发挥作用。我们假设，联合中和血管内皮生长因子和Treg可以产生强大的免疫调节作用，从而极大地提高疫苗治疗的效果。初步的临床实验数据支持我们的假设；在最近完成的一项初步研究中，我们观察到接受弱疫苗(未成熟的DC冲击肿瘤裂解液上清)与血管内皮生长因子阻滞剂和节律环磷酰胺联合的卵巢癌患者的客观放射学反应和66%的临床受益率为33%。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地测试这样一种假设，即通过阻断血管内皮生长因子结合Treg消耗来重新编辑肿瘤微环境可以使肿瘤疫苗达到临床效果。目的：1)进行肿瘤抗原致敏的自体树突状细胞疫苗联合抗血管内皮细胞生长因子抗体(Bevacizumab，Bevacizumab)合理联合Treg去除的初步临床试验。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)评价疫苗和联合免疫疗法在肿瘤周围和肿瘤微环境中的免疫效果。 公共卫生相关性：我们建议进行一项I/II期临床研究，以测试一种疫苗的联合免疫疗法，该疫苗包含所有可能的肿瘤抗原，外加阻断调节性T细胞的抗血管生成和免疫调节疗法。我们的假设是，癌症疫苗需要合理的组合，靶向并改变肿瘤微环境才能达到临床疗效。如果成功，我们将通过使许多肿瘤疫苗获得活性来极大地帮助癌症免疫治疗领域。

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.