Avirulent CD8+ T-cell Evading Oncolytic HSV-1 for the Treatment of Bladder Cancer

描述（由申请人提供）：溶瘤病毒（OV）治疗癌症采用双重作用机制，并具有两大优势。首先，OV被减毒，设计成在癌细胞中有效复制并仅杀死癌细胞，从而产生了很大的安全性。其次，正如在动物模型和人体试验中观察到的那样，OV通过肿瘤组织的复制和扩散使免疫系统靶向远处转移以消除肿瘤。这种双重作用机制结合了最有效的传统和新兴治疗方式的要素：选择性癌细胞细胞毒性和肿瘤疫苗接种。在这个应用中，我们提议评价BV-2711，一种新的单纯疱疹病毒1型（HSV1） OV。BV- 2711使用与OncoVEXGMCSF相同的溶瘤作用机制，但也编码内源性HSV1免疫逃避功能。在OncoVEXGMCSF治疗晚期转移性黑色素瘤的2期试验中，26%的患者对治疗有反应。重要的是，在所有应答者中，由于病毒诱导的肿瘤疫苗接种效果，未感染的转移灶减少或完全消失。当2期结果公布时，52%的应答者仍然存活，在治疗开始两年多后。OncoVEXGMCSF中使用的溶瘤机制导致HSV1 Us12基因的缺失，该基因通过MHC i类阻断病毒抗原在细胞表面的展示，已知Us12缺陷的HSV1被CD8+ t细胞过早清除。这可能导致OncoVEXGMCSF过早被清除，并限制了其在2期试验中的疗效。鉴于HSV1在人群中的高血清阳性率，逃避CD8+ t细胞可提高HSV1 OV的疗效。我们的假设是，内源性Us12基因的恢复，如BV-2711，将导致肿瘤减少和肿瘤疫苗接种效果的增加。在免疫功能低下的人类膀胱癌小鼠模型中的初步数据表明，BV-2711的溶瘤特性相当于OncoVEXGMCSF替代物。然而，由于这些小鼠缺乏t细胞，CD8+ t细胞逃避与OV疗效的相关性仍未确定。在这项应用中，我们建议在膀胱癌免疫能力小鼠模型中验证我们的假设。目的1。构建并评价一组基于bv -2711的OV优化免疫功能小鼠模型。目标2。BV-2711变异对膀胱癌小鼠模型的影响。

DESCRIPTION (provided by applicant): Oncolytic virus (OV) therapies for cancer employ a dual mechanism of action and have two major advantages. First, OV are attenuated and designed to efficiently replicate in and kill only cancer cells, creating a large safety profile. Second, as observed in animal models and human trials, OV replication and spread through tumor tissue programs the immune system to target distant metastases for elimination. This dual mechanism of action combines elements of the most effective traditional and emerging therapeutic modalities: selective cancer cell cytotoxicity and tumor vaccination. In this application, we propose to evaluate BV-2711, a novel Herpes Simplex Virus Type 1 (HSV1) OV. BV- 2711 utilizes the same oncolytic mechanism of action as OncoVEXGMCSF, but also encodes an endogenous HSV1 immune evasion function. In the Phase 2 trial of OncoVEXGMCSF in advanced metastatic melanoma, 26% of patients responded to therapy. Importantly, in all responders, uninfected metastases were reduced or disappeared entirely due to a virus-induced tumor vaccination effect. 52% of all responders were still alive when the Phase 2 results were published, more than two years after treatment initiation. The oncolytic mechanism used in OncoVEXGMCSF results in the deletion of the HSV1 Us12 gene, which blocks viral antigen display on the cell surface by MHC Class I. Us12-deficient HSV1 are known to be prematurely cleared by CD8+ T-cells. This likely resulted in premature clearance of OncoVEXGMCSF and limited its efficacy in the Phase 2 trial. Evasion of CD8+ T-cells could improve HSV1 OV efficacy, given the high seroprevalence of HSV1 in the population. It is our hypothesis that restoration of the endogenous Us12 gene, as in BV-2711, will lead to increased tumor reduction and tumor vaccination efficacy. Preliminary data in an immunocompromised mouse model of human bladder cancer demonstrated that the oncolytic properties of BV-2711 are equivalent to an OncoVEXGMCSF surrogate. However, because these mice lack T-cells, the relevance of CD8+ T-cell evasion to OV efficacy remains undetermined. In this application, we propose to test our hypothesis in immune competent mouse models of bladder cancer. Aim 1. Construct and evaluate a panel of BV-2711-based OV optimized for immune-competent mouse models. Aim 2. Evaluation of BV-2711 variants in syngeneic mouse model of bladder cancer. PUBLIC HEALTH RELEVANCE: Many forms of bladder cancer have limited options for therapy. In this proposal, we will develop and evaluate a virus for bladder cancer therapy that specifically targets cancer cells and uses the immune system to help in their clearance. We believe this could be safer and more effective that existing treatments.