Lessons from the OR: Using Clinical Biologic Correlates to Inform HSV Trial

利用临床生物学相关性指导HSV试验设计 通过该计划项目赠款，我们成功地生成并描述了几个新的、有希望的 基因工程单纯疱疹病毒(HSV)是临床试验中评估的候选病毒 恶性胶质瘤患者。这些病毒在体外和体外都得到了广泛的研究和表征。 体内模型，以证明安全性和有效性的原则证明。通过以下方式提高了疗效 (I)某些外源基因的表达和(Ii)放射辅助治疗。这个项目将利用我们的 第一代工程溶瘤单纯疱疹病毒G207一期临床试验体会 病毒(OHSV)在脑胶质瘤治疗中的应用。我们在第一次使用 基因工程HSV治疗人脑胶质瘤的三个I期临床试验中， 表达人IL-12的工程化HSV-1(M032)的研究即将开始。我们有 收集各种组织标本以描述接受治疗的人脑胶质瘤患者的生物反应 使用G207。我们建议将这些人类标本用于以下几个方面：目标1将确定IL-12 溶瘤单纯疱疹病毒表达对胶质瘤微环境和病毒复制的影响 这会影响肿瘤的反应。我们的G207试验和即将到来的M032试验的数据评估将是 将评估对治疗的反应和相应的发现，以寻找潜在的相关性。目标 2将确定HSV治疗的肿瘤是否具有由以下定义的SR、NSR或nu87基因表达谱 项目2以及这些GEP中是否有任何一个可以预测ILI2表达的治疗对肿瘤的反应 OHSV，以及确定与IL-1治疗后不良结果相关的额外GEP 12-表达OHSV。模拟这些反应的临床前模型将被开发来证实 对不同病毒结构和辅助治疗反应的可预测性。目标3将决定 胶质瘤前体细胞(GPC)对HSV溶瘤治疗应答的影响 GPC对病毒治疗有反应。同样，我们将评估IL-12表达对 GPC回应。目标4将作为下一种溶瘤单纯疱疹病毒(M032之后)进入临床的规划目标 从该计划项目中产生的试验。目标包括决策分析、选择要成为 与任何辅助治疗一起使用；启动试验前动物研究；以及开发临床 协议，cGMP病毒的生产，以及实际进行试验的额外资金申请。 相关性(参见说明)：我们已经进行了3个I期临床试验，试验对象为第一代溶瘤HSV 恶性胶质瘤患者和我们的结果证实了我们的观察结果，肿瘤基因的表达 曲线(GEP)定义了敏感性或抵抗力。这里提出的研究将分析来自 这些患者和那些接受我们第二代OHSV治疗的患者表达ILI2。 生物学研究，肿瘤GEP与OHSV应答的相关性将为设计新的OHSV提供信息，该OHSV可以 克服胶质瘤耐药因素，扩大OHSV在有效抗胶质瘤治疗中的适用性。

Using Clinical Biologic Correlates To Inform HSV Trial Design Through this Program Project grant we successfully generated and characterized several new, promising genetically engineered herpes simplex viruses (HSV) that are candidates for evaluation in clinical trials of patients with malignant glioma. These viruses were extensively studied and characterized in both in vitro and in vivo models to demonstrate proof-of-principle of safety and efficacy. Increased efficacy was provided by (i) expression of certain foreign genes and (ii) adjunctive therapy with radiation. This project will exploit our clinical trial experience in Phase I studies of G207, a first generation engineered oncolytic herpes simplex virus (oHSV) in the treatment of gliomas. We have developed extensive experience in the first use of a genetically engineered HSV for the treatment of human glioma in three Phase I clinical trials, with an upcoming study of a human IL-12 expressing engineered HSV-1 (M032) to begin imminently. We have collected a variety of tissue specimens to delineate the biologic response of human glioma patients treated with G207. We propose to use these human specimens for the following: AIM 1 will determine if IL-12 expression by oncolytic HSV produces differences in the glioma tumor microenvironment and viral replication that impact tumor response. Evaluation of data from our G207 trials and upcoming M032 trial will be undertaken; response to therapy and corresponding findings will be evaluated for potential correlations. AIM 2 will determine whether HSV-treated tumors have SR, NSR or nu87 gene expression profiles defined by Project 2 and whether any of these GEPs are predictive of tumor response to treatment with ILI2 expressing OHSV, as well as identifying additional GEPs that are associated with poor outcome after treatment with IL- 12-expressing oHSV. Preclinical models emulating these responses will be developed to confirm the predictability of response to different viral constructs and adjunctive therapies. AIM 3 will determine the impact of glioma progenitor cells (GPC) on response to oncolytic HSV therapy by contrasting the fraction of GPC present with the response to virus therapy. Similarly we will assess the effects of IL-12 expression on GPC response. Aim 4 will serve as a planning aim for the next oncolytic HSV (after M032) to enter clinical trials that emerges from this Program Project. The aim includes decision analysis selection of the virus to be used, along with any adjuvant therapies; initiation of pretrial animal studies; and development of a clinical protocol, production of cGMP virus, as well as application for additional funding to actually perform the trial. RELEVANCE (See instructions): We have undertaken 3 Phase I clinical trials with a first generation oncolytic HSV in patients with malignant glioma and our results have confirmed our observations that tumor gene expression profile (GEP) defines susceptibility or resistance. Studies proposed here will analyze tumor tissues from these patients and from those to be treated with our second generation oHSV, expressing ILI 2. From these biologic studies, correlation of tumor GEP with response to oHSV will inform design of new oHSV that can overcome glioma resistance factors and broaden applicability of oHSV for efficacious anti-glioma therapy.