Genetically Engineered Viruses for Prostate Cancer Therapy

描述(申请人提供)：单纯疱疹病毒-1(HSV-1)具有许多吸引人的特性，可作为前列腺癌治疗的溶瘤和基因转移载体进一步开发。尽管在过去的十年中在这一领域取得了许多进展，但我们现在描述了利用相关的模仿人类转移性前列腺癌的转基因前列腺癌模型来提高治疗效率的方法。我们假设，适当选择的化疗药物与溶瘤的HSV载体相结合将提高抗肿瘤效果，包括全身给药后，并且这种组合将允许使用较低剂量、毒性较低的化疗。我们将探讨静脉注射溶瘤单纯疱疹病毒的靶向性和抗肿瘤效果的机制。我们将研究HSV载体表达细胞因子的免疫机制，这些细胞因子可以协同作用诱导前列腺癌的免疫破坏。我们假设，溶瘤HSV载体通过抑制肿瘤内的血管生成发挥其抗肿瘤作用，并且适当选择的细胞因子的表达将增强这种抗血管生成作用。我们将在肿瘤内和静脉给药后探索这些作用机制。

DESCRIPTION (provided by applicant): Herpes simplex virus-1 (HSV-1) has many attractive features for further development as an oncolytic and gene transfer vector for prostate cancer therapy. Although many advances have been made in this field in the past decade, we now describe methods to increase the efficacy of treatment using relevant transgenic prostate cancer models mimicking human metastatic prostate cancer. We hypothesize that appropriately chosen chemotherapeutic agents combined with oncolytic HSV vectors will improve anti-tumor efficacy, including after systemic delivery, and that this combination will permit the use of lower, less toxic doses of chemotherapy. We will explore the mechanisms of targeting and anti-tumor efficacy of oncolytic HSV following intravenous delivery. We will study the immune mechanisms of HSV vectors expressing cytokines that can act synergistically to elicit immune destruction of prostate cancer. We hypothesize that oncolytic HSV vectors exert some of their anti-tumor effects by inhibiting angiogenesis within the tumor and that the expression of appropriately chosen cytokines will enhance this anti-angiogenic effect. We will explore these mechanisms of action following both intra-neoplastic and intravenous administration.