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

编码 PAP 的 DNA 疫苗在前列腺癌患者中的试点试验

• 批准号: 7527566
• 负责人: DOUGLAS G. MCNEEL
• 金额: $ 29.59万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7527566
• 关键词: Acid Phosphatase; Adverse event; Amino Acid Sequence; Androgens; Antibody Formation; Antigen Targeting; Antigens; CD8B1 gene; Cancer Etiology; Cancer Vaccines; Cessation of life; Clinical; Clinical Trials; DNA Vaccines; Development; Development, Other; Disease; Dose; End Point; Frequencies; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Human; Immune response; Immunization; Immunization Schedule; Immunologic Monitoring; Individual; Interferons; Label; Laboratories; Malignant neoplasm of prostate; Measures; Memory; Metastatic Prostate Cancer; Mission; NIH Program Announcements; National Cancer Institute; Neoplasm Metastasis; Outcome; Patients; Phase I Clinical Trials; Phase II Clinical Trials; Pilot Projects; Prostate; Prostate Cancer Vaccine; Prostatic Neoplasms; Proteins; Protocols documentation; Public Health; Randomized; Rate; Rattus; Recurrence; Research; Research Design; Research Personnel; Residual state; Resistance; Risk; Rodent Model; Safety; Schedule; Secondary Immunization; Staging; T memory cell; T-Lymphocyte; Testing; Time; Translating; Treatment Protocols; United States; Upper arm; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Week; cancer cell; cancer therapy; cohort; deprivation; design; improved; in vivo; men; pilot trial; plasmid DNA; prostatic fraction Acid phosphatase isoenzyme; research clinical testing; response; serum PSA; treatment duration; tumor

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.

描述（由申请人提供）：前列腺癌是一个重要的全球健康问题，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，作为治疗癌症，特别是前列腺癌的一种方法。我们的实验室一直在寻求确定合适的抗原以纳入前列腺癌疫苗，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。我们之前已经在大鼠身上证明，编码人类或大鼠PAP的DNA疫苗可以引发PAP特异性CD4+和CD8+ t细胞反应。分泌反应和抗体反应。此外，我们已经证明在前列腺癌患者中可以检测到PAP特异性的CD4+和CD8+ t细胞，这表明人类体内可以绕过对该蛋白的免疫耐受。我们还在复发性非转移性前列腺癌患者的剂量递增I期临床试验中研究了编码PAP的质粒DNA疫苗。在该试验中，我们没有观察到明显的不良事件，证明了在增加pap特异性CD8+ t细胞方面的免疫功效，并且在一些患者中观察到PSA倍增时间的增加。然而，关于维持长期效应和记忆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改善临床结果，问题仍然存在。当前方案的目标是评估同样的质粒DNA疫苗的安全性和免疫有效性，在一段较长的时间内，定期或根据持续免疫监测的定义进行加强免疫接种，以诱导和/或增强CD8+ t细胞效应和记忆免疫应答，以抵抗阉割，非转移性前列腺癌患者的PAP。一组受试者将按照以前的做法，每两周接种6次免疫，每隔3个月定期继续接种。另一组将接受6次双周免疫接种，然后根据pap特异性t细胞反应的存在与否进行加强免疫接种。这将是一项小型随机II期试验设计，每组15名受试者，在研究开始后一年内检测到80%的免疫应答率。研究设计将允许与我们之前的免疫应答率研究进行间接比较，并将以确定II期临床试验测试的最佳方法为目标。鉴于我们和其他人之前的研究表明，PAP诱导免疫应答可能与前列腺癌治疗的临床获益相关，次要终点将是评估其对PSA倍增时间和1年无转移生存期的影响。拟议临床试验的具体目的是：1)确定非转移性去势抵抗性前列腺癌患者连续皮内接种编码PAP的DNA疫苗（以GM-CSF作为疫苗佐剂）的安全性；2)确定pap特异性IFN？通过编码PAP的质粒DNA疫苗免疫，可在非转移性去势抵抗性前列腺癌患者中诱导CD8+ t细胞分泌和长期抗原特异性记忆；3)确定抗原特异性效应t细胞和记忆t细胞是否可以通过使用由免疫监测确定的个性化强化免疫时间表来增强。公共卫生相关性：前列腺癌是一个重大的全球健康问题，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升高的患者发展为进展性转移性疾病的风险很高。本研究的目的是开发有效的抗肿瘤DNA疫苗作为前列腺癌的治疗方法，并在该阶段前列腺癌患者的临床试验中具体评估疫苗。因此，该提案与国家癌症研究所的使命直接相关，也与本特定项目公告直接相关。此外，本建议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。