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: 8299604
• 负责人: JAMES M MARKERT
• 金额: $ 17.53万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299604
• 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; inclusion criteria; novel; phase 1 study; 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.

使用临床生物学关联以告知HSV试验设计 通过这个计划项目赠款，我们成功生成并表征了几个新的，有希望的 基因设计的单纯疱疹病毒（HSV）是在临床试验中进行评估的候选者 恶性神经胶质瘤患者。在体外和 体内模型以证明安全性和有效性的原则证明。提高功效由 （i）某些外源基因的表达和（ii）辐射的辅助治疗。这个项目将利用我们的 G207 I期研究的临床试验经验，第一代工程性溶瘤疱疹单纯疱疹 病毒（OHSV）治疗神经胶质瘤。我们已经在首次使用 在三期临床试验中治疗人神经胶质瘤的基因设计的HSV， 即将进行的人IL-12的研究表达工程的HSV-1（M032）即将开始。我们有 收集了各种组织标本，以描述接受治疗的人神经胶质瘤患者的生物学反应 与G207。我们建议将这些人类标本用于以下内容：AIM 1将确定IL-12是否是否 溶瘤HSV表达在神经胶质瘤微环境和病毒复制中产生差异 这会影响肿瘤反应。对我们的G207试验和即将进行的M032试验的数据评估将是 进行；对治疗和相应发现的反应将评估潜在的相关性。目的 2将确定HSV处理的肿瘤是否具有由SR，NSR或NU87基因表达曲线定义的 项目2以及这些GEP中的任何一个是否可以预测用表达ILI2治疗的肿瘤反应 OHSV，并确定与IL-治疗后结果不佳相关的其他GEP 12表达OHSV。将开发模拟这些响应的临床前模型，以确认 对不同病毒构建体和辅助疗法的反应的可预测性。 AIM 3将确定 神经胶质瘤祖细胞（GPC）的影响对溶瘤HSV治疗的反应通过对比 GPC对病毒疗法的反应呈现。同样，我们将评估IL-12表达对 GPC响应。 AIM 4将成为下一个溶瘤HSV（M032之后）进入临床的计划。 该计划项目出现的试验。目的包括病毒的决策分析选择为 与任何辅助疗法一起使用；审前动物研究的启动；和临床的发展 方案，CGMP病毒的产生，以及用于实际执行试验的额外资金。 相关性（请参阅说明）：我们已经在第一代Oncolytic HSV中进行了3期临床试验 恶性神经胶质瘤的患者和我们的结果已经证实了我们的观察到肿瘤基因表达 配置文件（GEP）定义了敏感性或阻力。这里提出的研究将分析来自 这些患者以及从第二代OHSV进行治疗的患者，表达ILI 2。 生物学研究，肿瘤GEP与对OHSV的响应的相关性将为新的OHSV设计提供信息 克服神经胶质瘤的抗性因子，并扩大了OHSV对有效抗脱光瘤疗法的适用性。