P53 Based Vaccine for Small Cell Lung Cancer

描述(申请人提供)：小细胞肺癌(SCLC)是一种不治之症，最具侵袭性的肺癌。小细胞肺癌经常与p53基因的体细胞突变相关，这往往导致肿瘤细胞中P53的过度表达。这种过度表达产生了各种抗原表位，形成了肿瘤特异性细胞免疫治疗的基础。肿瘤细胞的生存依赖于异常的P53蛋白，这使得该蛋白成为癌症免疫治疗的理想候选者。树突状细胞(DC)由于其独特的功能，是运送肿瘤抗原(AGS)的最佳载体。我们已经开发了一种新的疫苗，这种疫苗是基于用腺病毒构建的野生型P53转导树突状细胞(DC)。这种疫苗在临床前实验中显示出了效力。基于这些观察，我们启动了L/11期临床试验，旨在测试Ad.P53-DC疫苗在广泛分期的小细胞肺癌患者中的安全性和有效性。这场审判现在已经接近尾声。29名患者已进行了全面的临床和免疫学评估，另有21名患者正在进行评估。疫苗本身是安全的，并在两名患者身上产生了重大的肿瘤反应。在接受治疗的患者中，有一半的患者被疫苗诱导了P53特异性T细胞反应。因此，很大一部分患者对疫苗接种没有产生免疫学反应。我们的数据表明，对疫苗接种缺乏免疫反应与未成熟髓系细胞(IMC)的积累密切相关，此前已证明IMC具有免疫抑制作用。然而，试验的主要发现是在疫苗接种后立即接受化疗的患者中，主要目标肿瘤消退的频率异常高。这些观察结果是相当出乎意料的，因为现有的范例表明，化疗不利于维持免疫反应。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接受不同疫苗和化疗药物治疗的不同队列患者中的类似观察。这提示了癌症治疗的一个可能的新方向，即免疫治疗和化疗的直接顺序相结合可能会提供实质性的临床好处。所有以前的试验，包括我们的试验，都不是为了评估这一范式而设计的。我们认为，这一问题对整个实地具有极其重要的意义，应该得到明确的检验。因此，我们建议检验以下假设：(1)Ad.P53-DC疫苗与随后的化疗相结合将导致临床反应的显著改善，以及(2)在Ad.P53-DC疫苗中加入全反式维甲酸(ATRA)可显著改善小细胞肺癌患者的P53特异性免疫反应，从而显著提高临床反应。拟议的项目有两个具体目标。具体目的1.确定广泛期小细胞肺癌患者对ADV-P53 DC疫苗的临床反应，疫苗后给予化疗是否更有效，以及ALL-ATRA是否增强这种反应。具体目的2.确定免疫和化疗对P53特异性免疫的免疫调节作用。

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.