P5 - 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。 SCLC 常见 与 p53 基因突变有关，通常导致肿瘤细胞中 p53 过度表达。这种过度表达 产生多种抗原表位，构成肿瘤特异性细胞免疫治疗的基础。依赖性 肿瘤细胞依靠异常的 p53 来生存，使得这种蛋白质成为癌症免疫治疗的“理想”候选者。 由于其独特的功能，树突状细胞 (DC) 是递送肿瘤抗原 (Ag) 的最佳载体。我们 开发了一种基于使用腺病毒构建体用野生型 p53 转导 DC 的新疫苗。这个 疫苗在临床前实验中显示出效力。根据这些观察结果，我们进行了 l/ll 阶段 旨在测试 Ad.p53-DC 疫苗在广泛期患者中的安全性和有效性的临床试验 小细胞肺癌。该疫苗本身是安全的，并在两名患者身上产生了主要的肿瘤反应。 P53 特异性 T 细胞反应 一半的接受治疗的患者都受到疫苗的诱导。 。我们的数据表明，对于那些没有 对疫苗接种产生免疫反应，缺乏免疫反应与 未成熟骨髓细胞（ImC）的积累，先前已被证明具有免疫抑制作用。然而，主要 该试验的结果是，接受治疗的患者主要客观肿瘤消退的频率异常高。 接种疫苗后立即进行化疗。这些观察是相当出乎意料的，因为现有的范式 表明化疗不利于免疫反应的功效。在过去 8 个月中，四组 包括我们在内的几乎同时报告了在接受不同治疗的不同患者群体中的类似观察结果 疫苗和化疗药物。这表明癌症治疗可能有一个新方向，其中结合 直接顺序进行免疫治疗和化疗可能会带来显着的临床益处。之前所有的试验 包括我们的设计都不是为了评估这种范式。我们认为这个问题对于 整个领域值得进行明确的测试。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显着改善 临床反应，以及 (2) 在 Ad.p53-DC 疫苗中添加全反式视黄酸 (ATRA) 可能会显着提高 改善 p53 特异性免疫反应，从而改善 SCLC 患者的临床反应。拟议的项目有 两个具体目标。 具体目标 1. 确定广泛期患者对 Adv-p53 DC 疫苗的临床反应 SCLC，疫苗后给予化疗是否更有效，以及全 ATRA 是否可以增强这种效果 回应。 具体目标 2. 确定免疫和化疗对 p53 特异性的免疫调节作用 免疫力。

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.