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

使用临床生物学相关因素指导HSV试验设计 通过这项计划项目赠款，我们成功地产生和特点几个新的，有前途的 基因工程单纯疱疹病毒（HSV）是临床试验中评估的候选者， 恶性胶质瘤患者。这些病毒在体外和体外都进行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理证明。通过以下方式提高疗效： (i)某些外源基因的表达和（ii）放射的连续治疗。该项目将利用我们的 第一代工程化溶瘤性单纯疱疹病毒G207 I期临床试验经验 病毒（oHSV）治疗神经胶质瘤。我们在第一次使用 在三个I期临床试验中，基因工程HSV用于治疗人类胶质瘤， 即将进行的表达人IL-12的工程HSV-1（M032）的研究即将开始。我们有 收集了各种组织标本，以描述治疗的人类胶质瘤患者的生物学反应 在G207我们建议使用这些人类样本进行以下研究：AIM 1将确定IL-12是否 溶瘤性HSV的表达在神经胶质瘤肿瘤微环境和病毒复制中产生差异 影响肿瘤反应。将对我们的G207试验和即将进行的M032试验的数据进行评估， 进行;将评价对治疗的反应和相应结果的潜在相关性。目的 2将确定HSV处理的肿瘤是否具有SR、NSR或nu 87基因表达谱， 项目2以及这些GEP中的任何一个是否预测肿瘤对表达IL 12的治疗的应答 OHSV，以及识别与IL-10治疗后不良结局相关的其他GEP。 12-表达oHSV。将开发模拟这些反应的临床前模型，以确认 对不同病毒构建体和连续疗法的应答的可预测性。AIM 3将确定 胶质瘤祖细胞（GPC）对溶瘤HSV治疗反应的影响， GPC对病毒治疗有反应。类似地，我们将评估IL-12表达对细胞凋亡的影响。 GPC响应。目标4将作为下一个溶瘤HSV（M032之后）进入临床的计划目标 从这个项目中产生的试验。其目的包括对病毒的选择进行决策分析 沿着任何辅助治疗;试验前动物研究的开始;以及临床研究的开发 方案、cGMP病毒的生产以及申请额外资金以实际进行试验。 相关性（见说明书）：我们已经进行了3项第一代溶瘤HSV的I期临床试验， 我们的结果证实了我们的观察，肿瘤基因表达 GEP（generalprofile-general）定义了易感性或耐药性。这里提出的研究将分析来自 这些患者和用我们的表达ILI 2的第二代oHSV治疗的患者。从这些 生物学研究，肿瘤GEP与对oHSV应答的相关性将为设计新的oHSV提供信息， 克服胶质瘤耐药因子，拓宽oHSV用于有效抗胶质瘤治疗的适用性。

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.