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

OR 的经验教训：利用临床生物学相关性为 HSV 试验提供信息

• 批准号: 7747235
• 负责人: JAMES M MARKERT
• 金额: $ 18.01万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7747235
• 关键词: Adjuvant Therapy; Aftercare; Algorithms; Animals; Archives; Biology; Clinical; Clinical Protocols; Clinical Trials; Clinical Trials Design; Correlation Studies; Data; Decision Analysis; Development; Engineering; Evaluation; Exclusion Criteria; Funding; G207; Gene Expression; Gene Expression Profile; Generations; Genes; Glioma; Herpesvirus 1; Human; Immune response; In Situ; In Vitro; Instruction; Interleukin-12; Malignant Glioma; Molecular Profiling; Oncolytic; Outcome; Patients; Phase I Clinical Trials; Pre-Clinical Model; Predisposition; Program Research Project Grants; Radiation; Recurrence; Resistance; Role; Safety; Simplexvirus; Specimen; Stem cells; Tissues; Tumor Tissue; Validation; Viral; Virus; Virus Replication; base; cGMP production; design; experience; improved; in vivo Model; novel; programs; resistance factors; response; treatment planning; tumor

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.

利用临床生物学相关性为 HSV 试验设计提供信息 通过该计划项目拨款，我们成功地产生并描述了几个新的、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病毒 恶性胶质瘤患者。这些病毒在体外和体外都经过了广泛的研究和表征。 体内模型来证明安全性和有效性的原理证明。提高的功效是通过 (i) 某些外源基因的表达和 (ii) 放射辅助治疗。该项目将利用我们的 第一代工程溶瘤单纯疱疹病毒G207的I期研究临床试验经验 病毒（oHSV）治疗神经胶质瘤。我们在首次使用 在三项 I 期临床试验中，基因工程 HSV 用于治疗人类神经胶质瘤， 即将开始对表达人类 IL-12 的工程 HSV-1 (M032) 进行研究。我们有 收集了各种组织样本来描绘接受治疗的人类神经胶质瘤患者的生物反应 与G207。我们建议将这些人类样本用于以下目的：AIM 1 将确定 IL-12 是否 溶瘤 HSV 的表达会导致神经胶质瘤肿瘤微环境和病毒复制的差异 影响肿瘤反应。我们的 G207 试验和即将进行的 M032 试验的数据评估将 进行；将评估对治疗的反应和相应的发现的潜在相关性。目的 2 将确定 HSV 治疗的肿瘤是否具有 SR、NSR 或 nu87 基因表达谱，定义如下： 项目 2 以及这些 GEP 是否可以预测肿瘤对表达 ILI2 的治疗的反应 OHSV，以及识别与 IL-治疗后不良结果相关的其他 GEP 12-表达oHSV。将开发模拟这些反应的临床前模型来确认 对不同病毒结构和辅助疗法的反应的可预测性。 AIM 3 将确定 通过对比胶质瘤祖细胞 (GPC) 对溶瘤 HSV 治疗反应的影响 GPC 表现出对病毒治疗的反应。同样，我们将评估 IL-12 表达对 GPC 响应。目标4将作为下一个溶瘤HSV（M032之后）进入临床的规划目标 本计划项目中出现的试验。目的包括对病毒进行决策分析选择 与任何辅助疗法一起使用；启动审前动物研究；和临床开发 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（参见说明）：我们已在以下国家开展了 3 项针对第一代溶瘤 HSV 的 I 期临床试验： 恶性胶质瘤患者的研究结果证实了我们的观察结果，即肿瘤基因表达 概况（GEP）定义了敏感性或抵抗力。这里提出的研究将分析来自 这些患者以及接受我们的第二代 oHSV 治疗的患者，表达 ILI 2。 生物学研究，肿瘤 GEP 与 oHSV 反应的相关性将为新 oHSV 的设计提供信息，该新的 oHSV 可以 克服神经胶质瘤耐药因素并扩大 oHSV 在有效抗神经胶质瘤治疗中的适用性。