P53 Based Vaccine for Small Cell Lung Cancer

描述（由申请人提供）：小细胞肺癌（SCLC）是一种无法治愈的、侵袭性最强的肺癌。SCLC经常与p53基因的体细胞突变相关，而体细胞突变往往导致p53在肿瘤细胞中过表达。这种过表达产生多种抗原表位，形成肿瘤特异性细胞免疫治疗的基础。肿瘤细胞对异常p53的生存依赖使这种蛋白成为癌症免疫治疗的“理想”候选蛋白。树突状细胞（DC）由于其独特的特性，是肿瘤抗原（Ags）的最佳载体。我们已经开发了一种新的疫苗，基于树突状细胞（DC）的转导与野生型p53使用腺病毒结构。这种疫苗在临床前实验中显示出效力。基于这些观察，我们启动了一项i / ii期临床试验，旨在测试Ad的安全性和有效性。p53-DC疫苗在广泛分期SCLC患者中的应用这个试验现在差不多完成了。29例患者已完成临床及免疫学评价，另有21例患者正在评价中。疫苗本身是安全的，并在两名患者中产生了主要的肿瘤反应。在一半接受治疗的患者中，疫苗诱导了p53特异性T细胞反应。因此，相当大比例的患者对疫苗接种没有产生免疫反应。我们的数据表明，对疫苗接种缺乏免疫应答与未成熟髓样细胞（ImC）的积累密切相关，未成熟髓样细胞（ImC）先前被证明具有免疫抑制作用。然而，该试验的主要发现是，在接种疫苗后立即接受化疗的患者中，主要客观肿瘤消退的频率异常高。这些观察结果是相当出乎意料的，因为现有的范式表明化疗对免疫反应的维持是有害的。在过去的8个月里，包括我们在内的四个小组几乎同时报告了在不同队列中接受不同疫苗和化疗的患者的类似观察结果。这提示了癌症治疗的一个可能的新方向，即免疫治疗和化疗直接结合可能提供实质性的临床益处。包括我们在内的所有先前的试验都不是为了评估这种范式而设计的。我们认为，这个问题对整个领域具有至关重要的意义，值得进行最后的测试。因此，我们提出对以下假设进行检验：(1)广告组合。p53-DC疫苗和随后的化疗将导致临床反应的实质性改善，(2)在Ad中添加全反式维甲酸（ATRA）。p53-DC疫苗可显著提高SCLC患者的p53特异性免疫应答，从而提高临床应答。拟议的项目有两个具体目标。具体目标确定广泛期SCLC患者对Adv-p53 DC疫苗的临床反应，疫苗后给予化疗是否更有效，all-ATRA是否增强了这种反应。具体目标2。确定免疫和化疗对p53特异性免疫的免疫修饰作用。

DESCRIPTION (provided by applicant): Small cell lung cancer (SCLC) is the incurable, most aggressive form of lung cancer. SCLC has been found to be frequently associated with somatic mutations in the p53 gene that often results in p53 overexpression in tumor cells. This overexpression produces a variety of antigenic epitopes that form the basis for tumor specific cellular immunotherapy. Dependence of tumor cells on abnormal p53 for their survival makes this protein an "ideal" candidate for cancer immunotherapy. Because of their unique features, dendritic cells (DC) are the best vehicles for delivery of tumor antigens (Ags). We have developed a new vaccine based on transduction of dendritic cells (DC) with wild-type p53 using an adenoviral construct. This vaccine demonstrated potency in pre-clinical experiments. Based on those observation we initiated a phase l/ll clinical trial that was designed to test the safety and efficacy of the Ad.p53-DC vaccine in patients who have extensive stage SCLC. This trial is almost completed now. Twenty-nine patients were fully evaluated clinically and immunologically, and another 21 patients are in the process of evaluation. The vaccine itself was safe, and produced major tumor responses in two patients. P53-specific T cell responses were induced by the vaccine in half of the treated patients. Thus, a substantial proportion of patients did not develop an immunological response to vaccination. Our data demonstrated that the lack of immune response to vaccination was closely associated with accumulation of immature myeloid cells (ImC), previously shown to be immunosuppressive. However, the main findings from the trial were an unusually high frequency of major objective tumor regressions in patients treated with chemotherapy immediately after the vaccine. These observations were quite unexpected since the existing paradigm suggests that chemotherapy is detrimental to the maintenance of an immune response. During last 8 months, four groups including ours nearly simultaneously reported similar observations in different cohorts of patients treated with different vaccines and chemotherapeutics. This suggests a possible new direction in cancer treatment where the combination of immunotherapy and chemotherapy in direct sequence may provide substantial clinical benefits. All previous trials including ours were not designed to evaluate this paradigm. We believe that this issue is of a paramount significance for the entire field and deserves definitive testing. Therefore we propose to test the following hypotheses: (1) the combination of the Ad.p53-DC vaccine and subsequent chemotherapy will result in a substantial improvement in the clinical response, and (2) the addition of all-trans-retinoic acid (ATRA) to the Ad.p53-DC vaccine may substantially improve the p53-specific immune response and hence clinical response in SCLC patients. Proposed project has two specific aims. Specific Aim 1. Determine the clinical response to the Adv-p53 DC vaccine in patients with extensive stage SCLC, whether chemotherapy given after the vaccine is more effective, and whether all-ATRA enhances this response. Specific Aim 2. Determine the immune modifying effect of immunization and chemotherapy on p53-specific immunity.