Research Project
7502653
[unreadable] 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. [unreadable] [unreadable] [unreadable]
