PSMA-VRP vaccine for prostate cancer

描述（由申请人提供）：前列腺癌是美国男性中最常见的非皮肤癌，也是癌症死亡的第二大原因。雄激素消融提供了转移性疾病的一线治疗，但基本上所有肿瘤都成为激素难治性，然后迅速进展。唯一批准的非姑息性治疗难治性前列腺癌（HRPC）仅提供适度的生存获益，并伴有大量副作用。因此，迫切需要用于前列腺癌的新疗法。尽管前列腺癌具有显著的化学抗性，但基于其转移到免疫系统内的位点和相对较小的转移性病变大小，前列腺癌可能对免疫疗法敏感。我们已经开发了一种新的基于甲病毒的疫苗，该疫苗编码前列腺特异性膜抗原（PSMA），前列腺癌的标志性细胞表面标志物。PSMA在前列腺癌中大量且优先表达，而前列腺外表达有限。此外，PSMA表达随着疾病进展而增加，并且在转移性、难治性病例中最高。我们使用基于甲病毒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递送至免疫系统。甲病毒技术提供了许多优于其他基因递送系统的效力和安全性优势，包括打破动物对自身抗原的耐受性的能力。在I期SBIR FLAIR项目中，PSMA-VRP在小鼠中引起对PSMA的有效且持久的细胞和体液应答。PSMA-VRP还引发细胞毒性T淋巴细胞，其有效且特异性地杀死PSMA+靶细胞，并且该产品在符合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。总的来说，PSMA-VRP已经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推进到人体测试中，作为甲病毒VRP技术在肿瘤学中的首次应用。该II期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，以确保人体试验的监管批准。1期临床试验将评估递增剂量的PSMA-VRP的耐受性、免疫原性和初步抗肿瘤作用。将使用灵敏的SOP驱动的免疫监测方法测量免疫应答，该方法改编自我们临床前研究中成功使用的方法。该项目将为新型甲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提供基本见解。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。雄激素消融提供了转移性疾病的一线治疗，但基本上所有肿瘤都成为激素难治性，然后迅速进展。唯一批准的非姑息性治疗难治性前列腺癌（HRPC）仅提供适度的生存获益，并伴有大量副作用。因此，迫切需要用于前列腺癌的新疗法。尽管前列腺癌具有显著的化学抗性，但基于其转移到免疫系统内的位点和相对较小的转移性病变大小，前列腺癌可能对免疫疗法敏感。

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.