Vaccine-Dac/Bev Combinatorial Therapy in Ovarian Cancer

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，卵巢癌可以接受免疫治疗。我们的研究表明，肿瘤浸润效应T细胞预测卵巢癌患者预后改善，而肿瘤浸润Treg细胞预测卵巢癌患者生存期缩短。然而，迄今为止，癌症疫苗产生的效果并不明显。我们的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阻止了抗肿瘤效应T细胞的植入、扩增和功能；a)肿瘤血管内皮形成血肿瘤屏障，阻止效应T细胞外渗进入肿瘤（通过下调细胞粘附分子），或杀死肿瘤外渗的T细胞（通过fasl介导的细胞凋亡）；b)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CCR10+ Treg细胞的积累，而Treg反过来表达高水平的VEGF。因此，虽然VEGF阻断可以减弱血肿瘤屏障，但也可以使肿瘤微环境中Treg积累反弹增加，保持耐受性。在这种情况下，抑制Treg可以使肿瘤失去一个关键的稳态耐受机制，并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微弱的抗肿瘤免疫应答成为临床有效的。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dc脉冲肿瘤裂解液上清液）联合VEGF阻断剂和环磷酰胺治疗的卵巢癌患者有33%的客观放射学反应和66%的临床获益率。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假设，即通过VEGF阻断联合Treg消耗重新编辑肿瘤微环境可以使肿瘤疫苗达到临床疗效。提出以下目标：目标1)利用脱白细胞didititox （Ontak）和抗vegf抗体贝伐单抗（Bevacizumab）合理联合Treg耗竭的自体全肿瘤抗原脉冲树突状细胞疫苗临床先导试验。目的2)评价疫苗联合免疫治疗的安全性、可行性及临床效果。目的3)评价疫苗和组合免疫治疗在外周和肿瘤微环境的免疫效果。

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.