PSMA-VRP vaccine for prostate cancer

描述(申请人提供)：前列腺癌是美国男性最常见的非皮肤癌，也是导致癌症死亡的第二大原因。雄激素消融为转移性疾病提供了一线治疗，但基本上所有的肿瘤都是激素耐药的，然后迅速发展。唯一被批准的激素难治性前列腺癌(HRPC)的非姑息疗法只提供了适度的生存益处和大量的副作用。因此，迫切需要前列腺癌的新疗法。尽管前列腺癌具有明显的化疗耐药性，但由于其转移到免疫系统内的部位以及转移灶相对较小，因此可能对免疫治疗敏感。我们已经开发出一种新型的基于甲型病毒的疫苗，它编码前列腺癌的标志性细胞表面标志--前列腺特异性膜抗原(PSMA)。PSMA在前列腺癌中大量且优先表达，但前列腺外表达有限。此外，PSMA的表达随着疾病的进展而增加，在转移性、激素不敏感的病例中表达最高。我们使用基于委内瑞拉马脑炎病毒(VEE)的非复制型疫苗复制子颗粒(VRP)将PSMA输送到免疫系统。与其他基因传递系统相比，甲型病毒技术具有许多效力和安全性优势，包括打破动物对自身抗原的耐受性。在第一阶段SBIR FLAIR项目中，PSMA-VRP在小鼠中激发了对PSMA的强大和持久的细胞和体液反应。PSMA-VRP还可以诱导细胞毒性T淋巴细胞，对PSMA+靶细胞具有强大的特异性杀伤作用，该产品在符合GLP的安全性研究中显示出令人鼓舞的安全性和生物分布特征。总体而言，PSMA-VRP已显示出明显优于其他疫苗策略的优势。在这里，我们建议将PSMA-VRP技术应用于人体试验，作为甲病毒VRP技术在肿瘤学中的首次应用。这一第二阶段项目的总体目标是在HRPC患者中进行PSMA-VRP的首次人体试验。我们将完成关键的临床前研究，并准备必要的文件，以确保人体试验获得监管批准。1期临床试验将评估PSMA-VRP递增剂量的耐受性、免疫原性和初步抗肿瘤效果。免疫反应将使用敏感的SOP驱动的免疫监测方法进行测量，这些方法与我们临床前研究中成功使用的方法相适应。该项目将从根本上洞察一种新的甲型病毒疫苗递送技术和PSMA作为前列腺癌主动免疫治疗靶点的潜在治疗效用。该项目的成功将为这种治疗晚期前列腺癌的创新疗法提供初步的概念验证。前列腺癌是美国男性最常见的非皮肤癌，也是癌症死亡的第二大原因。雄激素消融为转移性疾病提供了一线治疗，但基本上所有的肿瘤都是激素耐药的，然后迅速发展。唯一被批准的激素难治性前列腺癌(HRPC)的非姑息疗法只提供了适度的生存益处和大量的副作用。因此，迫切需要前列腺癌的新疗法。尽管前列腺癌具有明显的化疗耐药性，但由于其转移到免疫系统内的部位以及转移灶相对较小，因此可能对免疫治疗敏感。

DESCRIPTION (provided by applicant): Prostate cancer is the most common non-cutaneous cancer and second leading cause of cancer death in American males. Androgen ablation provides first-line therapy of metastatic disease, but essentially all tumors become hormone refractory and then rapidly progress. The only approved non-palliative therapy for hormone-refractory prostate cancer (HRPC) provides only a modest survival benefit with substantial side effects. Thus, there is an urgent need for novel therapies for prostate cancer. Although notably chemoresistant, prostate cancer may be susceptible to immune therapies based on its metastasis to sites within the immune system and the relatively small size of metastatic lesions. We have developed a novel alphavirus-based vaccine that encodes prostate-specific membrane antigen (PSMA), the hallmark cell-surface marker of prostate cancer. PSMA is abundantly and preferentially expressed in prostate cancer with limited extraprostatic expression. Furthermore, PSMA expression increases with disease progression and is highest in metastatic, hormone-refractory cases. We deliver PSMA to the immune system using a non-replicating Vaccine Replicon Particle (VRP) based on the alphavirus Venezuelan Equine Encephalitis virus (VEE). Alphavirus technology offers a number of potency and safety advantages over other gene-delivery systems, including an ability to break tolerance to self- antigens in animals. In the Phase I SBIR FLAIR project, PSMA-VRP elicited potent and durable cellular and humoral responses to PSMA in mice. PSMA-VRP also elicited cytotoxic T lymphocytes that potently and specifically killed PSMA+ target cells, and the product has demonstrated encouraging safety and biodistribution profiles in GLP-compliant safety studies. Overall, PSMA-VRP has demonstrated clear advantages over other vaccine strategies. Here, we propose to advance PSMA-VRP into human testing as the first application of alphavirus VRP technology in oncology. The overall goal of this Phase II project is to conduct the first-in-man trial of PSMA- VRP in patients with HRPC. We will complete critical preclinical studies and prepare documents required to secure regulatory approval for human testing. The phase 1 clinical trial will evaluate the tolerability, immunogenicity and preliminary anti-tumor effects of escalating doses of PSMA-VRP. Immune responses will be measured using sensitive SOP-driven immunomonitoring methods adapted from those successfully used in our preclinical studies. This project will provide fundamental insight into the potential therapeutic utility both of a novel alphavirus vaccine delivery technology and of PSMA as a target for active immunotherapy of prostate cancer. Success in the project would provide initial proof-of-concept for this innovative therapy for advanced prostate cancer. Prostate cancer is the most common non-cutaneous cancer and second leading cause of cancer death in American males. Androgen ablation provides first-line therapy of metastatic disease, but essentially all tumors become hormone refractory and then rapidly progress. The only approved non-palliative therapy for hormone-refractory prostate cancer (HRPC) provides only a modest survival benefit with substantial side effects. Thus, there is an urgent need for novel therapies for prostate cancer. Although notably chemoresistant, prostate cancer may be susceptible to immune therapies based on its metastasis to sites within the immune system and the relatively small size of metastatic lesions.