P-53-Based Vaccine for Small Cell Lung Cancer

广泛期小细胞肺癌(SCLC)是一种无法治愈的侵袭性肺癌。小细胞肺癌经常 与P53基因突变有关，该突变通常导致肿瘤细胞中P53的过度表达。这种过度表达 产生各种抗原表位，形成肿瘤特异性细胞免疫治疗的基础。依赖于 肿瘤细胞对异常的P53蛋白的生存使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，该疫苗是基于用腺病毒构建的野生型p53转导DC的。这 疫苗在临床前实验中显示出了效力。在这些观察的基础上，我们进行了阶段L/11 旨在测试Ad.P53-DC疫苗在具有广泛分期的患者中的安全性和有效性的临床试验 SCLC。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。P53特异性T细胞反应 在接受治疗的患者中，有一半是由疫苗诱导的。。我们的数据表明，对于那些没有 对接种疫苗产生免疫反应，与免疫反应的缺乏密切相关 未成熟的髓样细胞(IMC)堆积，以前显示为免疫抑制。然而，主要的 试验的结果是，在接受治疗的患者中，主要目标肿瘤消退的频率异常高。 疫苗接种后立即进行化疗。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疗效是有害的。在过去的8个月里，四个小组 包括我们几乎同时报道的在不同队列中接受不同治疗的患者中的类似观察 疫苗和化疗药物。这提示了癌症治疗的一个可能的新方向，即联合应用 免疫治疗和直接序贯化疗可能会带来实质性的临床益处。所有以前的试验 包括我们的设计都不是为了评估这个范例。我们认为，这一问题对 整个领域，值得进行最终的测试。因此，我们建议检验以下假设：(1) 将Ad.P53-DC疫苗与随后的化疗相结合将导致显著改善 临床反应，以及(2)将全反式维甲酸(ATRA)添加到Ad.P53-DC疫苗中可以实质上 改善小细胞肺癌患者的P53特异性免疫反应，从而改善临床反应。拟议中的项目具有 有两个明确的目标。 具体目的1.确定广泛期患者对AdV-P53 DC疫苗的临床反应 小细胞肺癌，疫苗后给予的化疗是否更有效，以及全反式维甲酸是否增强了这一点 回应。 特定目的2.确定免疫和化疗对P53特异性的免疫调节作用 豁免权。

Extensive stage small cell lung cancer (SCLC) is an incurable, aggressive form of lung cancer. SCLC is frequently associated with mutations in the p53 gene that often result 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 DC with wild-type p53 using an adenoviral construct. This vaccine demonstrated potency in pre-clinical experiments. Based on those observations we performed a phase l/ll clinical trial designed to test the safety and efficacy of the Ad.p53-DC vaccine in patients who have extensive stage SCLC. 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. . Our data demonstrated that for those patients who did not develop an immunological response to vaccination, the lack of immune response 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 efficacy 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 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. The 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.