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

无毒 CD8 T 细胞逃避溶瘤 HSV-1 用于治疗膀胱癌

• 批准号: 8395350
• 负责人: Matthew Charles Mulvey
• 金额: $ 22.27万
• 依托单位: BENEVIR BIOPHARM, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-13 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8395350
• 关键词: Affect; Aftercare; Animal Model; Antigen Presentation; Antigen-Presenting Cells; Attenuated; CD8B1 gene; Cancer Model; Cattle; Cell surface; Contralateral; Cytolysis; Data; Distant Metastasis; Elements; Evaluation; Exhibits; Generations; Genes; Granulocyte-Macrophage Colony-Stimulating Factor; Herpesviridae; Herpesvirus 1; Human; I-antigen; Immune; Immune system; Immunocompromised Host; Implant; Individual; Infiltration; Lead; Licensing; MHC Class I Genes; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Metastatic Melanoma; Modality; Mus; Neoplasm Metastasis; New York; Oncolytic; Oncolytic viruses; Patients; Phase; Phase II Clinical Trials; Population; Preparation; Property; Publishing; Recombinants; Rodent; Safety; Seroprevalences; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Tumor Antigens; Tumor Tissue; Universities; Vaccination; Variant; Viral; Viral Antigens; Viral Tumor Antigens; Virus; Virus Replication; antigenic peptide transporter; base; cancer cell; cancer therapy; cell killing; cytotoxicity; design; improved; inhibitor/antagonist; killings; mouse model; novel; phase 3 study; polypeptide; premature; programs; restoration; small molecule; tumor

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.

描述（由申请人提供）：用于癌症的溶瘤病毒（OV）疗法采用双重作用机制并具有两个主要优点。首先，OV 是减毒的，旨在有效地复制并仅杀死癌细胞，从而产生很大的安全性。其次，正如在动物模型和人体试验中观察到的那样，OV 复制并通过肿瘤组织扩散，从而使免疫系统能够瞄准远处转移以进行消除。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：选择性癌细胞毒性和肿瘤疫苗接种。在此应用中，我们建议评估 BV-2711，一种新型单纯疱疹病毒 1 型 (HSV1) OV。 BV-2711 利用与 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应，未感染的转移瘤均减少或完全消失。当第二阶段结果公布时，即治疗开始两年多后，52% 的反应者仍然活着。 OncoVEXGMCSF 中使用的溶瘤机制导致 HSV1 Us12 基因缺失，从而阻止 I 类 MHC 在细胞表面展示病毒抗原。已知 Us12 缺陷的 HSV1 会被 CD8+ T 细胞过早清除。这可能导致 OncoVEXGMCSF 过早清除并限制其在 2 期试验中的疗效。鉴于人群中 HSV1 的高血清流行率，CD8+ T 细胞的逃避可以提高 HSV1 OV 的功效。我们假设内源性 Us12 基因的恢复（如 BV-2711 中那样）将导致肿瘤缩小和肿瘤疫苗接种功效增加。人类膀胱癌免疫功能低下小鼠模型的初步数据表明，BV-2711 的溶瘤特性与 OncoVEXGMCSF 替代品相当。然而，由于这些小鼠缺乏 T 细胞，CD8+ T 细胞逃避与 OV 功效的相关性仍不确定。在本申请中，我们建议在具有免疫能力的膀胱癌小鼠模型中检验我们的假设。目标 1. 构建并评估一组针对具有免疫功能的小鼠模型进行优化的基于 BV-2711 的 OV。目标 2. 在同基因小鼠膀胱癌模型中评估 BV-2711 变体。 公共卫生相关性：许多形式的膀胱癌的治疗选择有限。在这项提案中，我们将开发和评估一种用于膀胱癌治疗的病毒，该病毒专门针对癌细胞并利用免疫系统帮助清除癌细胞。我们相信这比现有的治疗方法更安全、更有效。