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

描述（由申请人提供）：前列腺癌是一个重要的全球性健康问题，需要新的治疗方法。这项研究的目标是开发抗前列腺肿瘤疫苗作为癌症，特别是前列腺癌的治疗方法。我们的实验室一直在寻求定义合适的抗原纳入前列腺癌疫苗，靶向这些抗原在啮齿动物模型中使用质粒DNA疫苗，并最终将这些发现转化为人类前列腺癌患者的临床试验。我们和其他研究人员已经将我们的初步努力集中在前列腺酸性磷酸酶（PAP）作为前列腺肿瘤疫苗抗原上。我们以前已经证明，在大鼠中，编码人或大鼠PAP的DNA疫苗可以引起PAP特异性的CD 4+和CD 8 + T细胞反应，IFN？分泌反应和抗体反应。此外，我们已经表明，PAP特异性的CD 4+和CD 8 + T细胞可以在前列腺癌患者中检测到，这表明对这种蛋白质的免疫耐受性可以在人体内规避。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。在该试验中，我们没有观察到显著的不良事件，证明了增强PAP特异性CD 8 + T细胞的免疫功效，并观察到几名患者的PSA倍增时间增加。然而，关于维持长期效应和记忆T细胞应答的最佳免疫频率以及这些长期应答的发展是否会导致改善的临床结果，仍然存在问题。当前方案的目的是评价该相同质粒DNA疫苗的安全性和免疫学疗效，该疫苗在较长时间内以定期间隔给予加强免疫或根据持续免疫监测的定义给予加强免疫，以诱导和/或增强去势抵抗性非转移性前列腺癌患者对PAP的CD 8 + T细胞效应和记忆免疫应答。一个受试者队列将接受6次每两周一次的免疫接种，如前所述，免疫接种以3个月的定期间隔持续进行。另一组将接受6次每两周一次的免疫接种，然后按照存在或不存在PAP特异性T细胞应答定义的时间表进行加强免疫接种。这将是一项小型、随机II期试验设计，每个队列15例受试者，研究开始后1年检测免疫应答率为80%。该研究设计将允许与我们先前的研究在免疫应答率方面进行间接比较，并将确定II期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，诱导对PAP的免疫应答可能与前列腺癌治疗的临床获益相关，次要终点将是评价对PSA倍增时间和1年无转移生存期的影响。拟议的临床试验的具体目的是：1）确定在非转移性去势抵抗性前列腺癌患者中，以GM-CSF作为疫苗佐剂，连续皮内接种编码PAP的DNA疫苗的安全性; 2）确定PAP特异性IFN？分泌性CD 8 + T细胞和长期抗原特异性记忆性CD 8 + T细胞可以通过用编码PAP的质粒DNA疫苗免疫接种在患有非转移性去势抵抗性前列腺癌的患者中引发;和3）确定抗原特异性效应和记忆性T细胞是否可以通过使用由免疫监测确定的加强免疫的个体化时间表来增强。公共卫生相关性：前列腺癌是一个重要的全球性健康问题，也是美国男性癌症相关死亡的第二大原因。雄激素剥夺治疗后血清PSA升高的患者发生进展性转移性疾病的风险较高。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，并在临床试验中专门评估该阶段前列腺癌患者的疫苗。因此，本提案与国家癌症研究所的使命直接相关，并与本具体计划公告直接相关。此外，该提案的目标是确定免疫监测是否可用于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，这与其他抗肿瘤疫苗的开发有关。

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.