Pilot trial of a DNA vaccine encoding PAP in patients with prostate cancer

描述(申请人提供)：前列腺癌是一个重要的世界性健康问题，需要新的治疗方法。这项研究的目标是开发抗前列腺癌疫苗作为癌症的治疗方法，特别是前列腺癌。我们的实验室一直在寻求确定前列腺癌疫苗中包含的合适抗原，使用质粒DNA疫苗在啮齿动物模型中靶向这些抗原，并最终将这些发现转化为前列腺癌患者的人类临床测试。我们和其他研究人员将最初的努力集中在前列腺酸性磷酸酶(PAP)作为前列腺癌疫苗抗原上。我们之前已经在大鼠身上证明，编码人或大鼠PAP的DNA疫苗可以激发PAP特异性的CD4+和CD8+T细胞反应，干扰素？分泌反应和抗体反应。此外，我们已经证明，前列腺癌患者体内可以检测到PAP特异性的CD4+和CD8+T细胞，这表明在人体内可以避免对这种蛋白的免疫耐受。我们还研究了编码PAP的质粒DNA疫苗在复发性非转移性前列腺癌患者中的剂量递增I期临床试验。在这项试验中，我们没有观察到明显的不良反应，证明了增强PAP特异性CD8+T细胞的免疫学效果，并观察到几名患者的PSA倍增时间增加。然而，对于维持长期效应和记忆性T细胞反应的最佳免疫频率，以及这些长期反应的发展是否会导致临床结果的改善，仍然存在疑问。当前方案的目标将是评估这种相同的质粒DNA疫苗的安全性和免疫学效果，这种疫苗在长时间内给予定期或持续免疫监测的加强免疫，以诱导和/或增强对去势耐受、非转移性前列腺癌患者的CD8+T细胞效应和记忆免疫反应。与以前一样，一组受试者将接受六次双周免疫接种，每隔三个月定期进行一次免疫接种。另一组将接受六次双周免疫治疗，然后按照有无PAP特异性T细胞反应确定的时间表进行加强免疫。这将是一项小规模、随机的II期试验设计，每个队列有15名受试者，在研究开始一年后检测80%的免疫应答率。这项研究设计将允许与我们之前的研究在免疫反应率方面进行间接比较，目标是确定第二阶段临床试验测试的最佳方法。鉴于我们和其他人之前进行的研究表明，诱导PAP的免疫反应可能与前列腺癌治疗的临床益处有关，次要终点将评估PSA倍增时间和1年无转移生存率的影响。拟议临床试验的具体目标将是：1)确定编码PAP的DNA疫苗在非转移性去势抵抗型前列腺癌患者中的安全性；2)确定是否可以通过编码PAP的质粒型DNA疫苗免疫，在非转移性去势抵抗型前列腺癌患者中诱导出分泌PAP特异性干扰素的CD8+T细胞和长期抗原特异性记忆CD8+T细胞；以及3)确定是否可以通过使用由免疫学监测确定的个体化加强免疫方案来增强抗原特异性效应器和记忆性T细胞。公共卫生相关性：前列腺癌是一个重大的世界性健康问题，也是美国男性癌症相关死亡的第二大原因。去雄激素治疗后血清PSA升高的患者发生进展性转移性疾病的风险很高。这项研究的目标是开发有效的抗肿瘤DNA疫苗作为前列腺癌的治疗方法，并在这一阶段的前列腺癌患者的临床试验中专门评估疫苗。因此，这项建议与国家癌症研究所的使命直接相关，并与这一特定计划的宣布直接相关。此外，这项提案的目标是确定是否可以使用免疫监测来指导正在进行的疫苗治疗计划，以最终确定最佳治疗计划。因此，这对其他抗肿瘤疫苗的开发具有重要意义。

DESCRIPTION (provided by applicant): Prostate cancer is a significant worldwide health problem for which new treatments are needed. The goal of this research is to develop anti-prostate tumor vaccines as a treatment for cancer, and specifically prostate cancer. Our laboratory has been seeking to define appropriate antigens for inclusion in prostate cancer vaccines, target these antigens in rodent models using plasmid DNA vaccines, and ultimately to translate these findings to human clinical testing in patients with prostate cancer. We and other investigators have focused our initial efforts on prostatic acid phosphatase (PAP) as a prostate tumor vaccine antigen. We have previously demonstrated in rats that DNA vaccines encoding either human or rat PAP can elicit PAP-specific CD4+ and CD8+ T-cell responses, IFN? secreting responses, and antibody responses. Moreover, we have shown that CD4+ and CD8+ T-cells specific for PAP can be detected in patients with prostate cancer, suggesting that immunological tolerance to this protein can be circumvented in vivo in humans. We have also investigated a plasmid DNA vaccine encoding PAP in a dose-escalation phase I clinical trial in patients with recurrent non-metastatic prostate cancer. In that trial we observed no significant adverse events, demonstrated immunological efficacy in augmenting PAP-specific CD8+ T-cells, and observed an increase in PSA doubling time in several patients. Questions remain, however, as to the optimal frequency of immunization to maintain long-term effector and memory T-cell responses, and whether the development of these long-term responses will result in improved clinical outcomes. The goal of the current protocol will be to evaluate the safety and immunological efficacy of this same plasmid DNA vaccine, administered over a prolonged period of time with booster immunizations given at regular intervals or as defined by ongoing immune monitoring, to induce and/or augment CD8+ T-cell effector and memory immune responses to PAP in patients with castrate-resistant, non-metastatic prostate cancer. One cohort of subjects will be treated with six bi-weekly immunizations, as previously conducted, with immunizations continuing at regular 3-month intervals. The other cohort will be treated with six bi-weekly immunizations followed by booster immunizations at a schedule defined by the presence or absence of PAP-specific T-cell responses. This will be a small, randomized phase II trial design with fifteen subjects per cohort, powered to detect an immune response rate of 80% at one year after study initiation. The study design will permit an indirect comparison with our previous study with respect to immune response rates, and will have the goal of identifying an optimal approach for phase II clinical trial testing. Given that previous studies conducted by us and others have suggested that the induction of immune responses to PAP may be associated with clinical benefit in the treatment of prostate cancer, secondary endpoints will be to evaluate the effect on PSA doubling time and 1-year metastasis-free survival. The specific aims of the proposed clinical trial will be 1) to determine the safety of serial intradermal vaccinations of a DNA vaccine encoding PAP, with GM-CSF as a vaccine adjuvant, in patients with non-metastatic castrate-resistant prostate cancer; 2) to determine whether PAP-specific IFN?-secreting CD8+ T-cells and long-term antigen-specific memory CD8+ T-cells can be elicited in patients with non-metastatic castrate-resistant prostate cancer by means of immunization with a plasmid DNA vaccine encoding PAP; and 3) to determine if antigen-specific effector and memory T-cells can be augmented by using individualized schedules of booster immunizations determined by immunological monitoring. PUBLIC HEALTH RELEVANCE: Prostate cancer is a significant worldwide health problem, and the second leading cause of cancer-related death in men in the United States. Patients with rising serum PSA after androgen deprivation therapy are at high risk for developing progressive, metastatic disease. The goal of this research is to develop effective anti-tumor DNA vaccines as a treatment for prostate cancer, and to specifically evaluate a vaccine in a clinical trial for patients with this stage of prostate cancer. Thus, this proposal is directly relevant to the mission of the National Cancer Institute, and directly relevant to this specific Program Announcement. In addition, the goal of this proposal is to determine if immune monitoring can be used to guide the ongoing schedule of treatment with a vaccine, to ultimately define an optimal schedule of treatment. This is consequently relevant to the development of other anti-tumor vaccines.