Utilization of Immuno-PET to detect response and guide novel oHSV-based therapy for glioma

利用免疫 PET 检测反应并指导基于 oHSV 的新型神经胶质瘤治疗

• 批准号: 10635507
• 负责人: JAMES M MARKERT
• 金额: $ 57.14万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635507
• 关键词: Biological; Biological Assay; Biopsy; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Cycle Kinetics; Cells; Characteristics; Clinical; Combined Modality Therapy; Cytolysis; Data; Disease Progression; Dose; Flow Cytometry; Glioblastoma; Glioma; Goals; Granzyme; Heterogeneity; Human; IL18 gene; Image; Immune; Immune checkpoint inhibitor; Immune response; ImmunoPET; Immunofluorescence Immunologic; Immunologic Stimulation; Immunologics; Immunotherapy; Infection; Infiltration; Inflammation; Interleukin-12; Kinetics; Knowledge; Laboratories; Magnetic Resonance Imaging; Malignant - descriptor; Malignant neoplasm of brain; Measures; Modeling; Molecular; Mus; Patient Selection; Patients; Phase I Clinical Trials; Positron-Emission Tomography; Pre-Clinical Model; Prediction of Response to Therapy; Proteins; Radiation; Radiation therapy; Regimen; Signal Transduction; Solid Neoplasm; T cell infiltration; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Treatment Efficacy; Tumor Antigens; Tumor Volume; Validation; Viral Antigens; Virus; Visualization; anti-tumor immune response; booster vaccine; cell transformation; combinatorial; imaging modality; immune cell infiltrate; immunoregulation; improved; in vivo; insight; molecular imaging; mouse model; neoplastic cell; novel; oncolytic herpes simplex virus; pre-clinical; predicting response; programmed cell death ligand 1; programmed cell death protein 1; quantitative imaging; response; serial imaging; synergism; transcriptomics; treatment optimization; treatment response; tumor

PROJECT SUMMARY The overarching goal of this project is to quantify the temporal kinetics of T-cell activation and infiltration during novel combination intratumoral oncolytic herpes simplex virus (oHSV) immunotherapy with advanced molecular immuno- positron emission tomography (PET) imaging in preclinical models of glioblastoma (GBM). Novel targeted oHSV immunotherapy has been shown to directly kill GBM tumor cells as the virus selectively replicates within and lyses malignantly transformed cells, however there is a knowledge gap in understanding the kinetics of the immune cell changes and how to harness those changes to improve therapeutic efficacy. As inflammation and pseudo progression are key characteristics of immunotherapy-induced tumor changes, standard imaging methods fail to provide reliable response assessments, which can sometimes take up to six months to reveal through clinical changes in tumor size. Advanced quantitative imaging strategies can provide spatial and temporal information on biological alterations prior to the clinically observed, downstream changes in tumor size. Immuno- PET imaging could stratify selection of patients who pursue immunotherapy and guide the timing and sequencing of combinatorial therapies. We have preliminary data showing that there are differential responses in CD8 expression in gliomas during oHSV therapy and that oHSV increases CD8 infiltration, as we can image these changes with PET. Further, preliminary evidence shows that granzyme B increases (as measured by GZP-PET) are related to overall tumor response. The overarching hypothesis is PET molecular imaging can guide targeted IL-12 and IL-18 oHSV to enhance therapeutic efficacy and extend survival in preclinical models of GBM. There are three specific aims to answer this hypothesis: Aim 1. Using advanced molecular immunoPET in GBM murine models with biological validation, determine if early T-cell kinetics of infiltration and activation are increased following oHSV therapy alone, or with oHSV expressing IL-12 and/or IL- 18. We will quantify longitudinal alterations in T-cell infiltration with [89Zr]-CD8-PET imaging of CD8+ cells and quantify longitudinal alterations in T-cell activation (granzyme B) with [68Ga]-GZP-PET imaging. Aim 2. Using advanced molecular immunoPET in GBM murine models, determine if secondary therapeutics (radiation therapy, or immunomodulatory immune checkpoint inhibitors) used in combination with oHSV IOT produce increased intermediate term T cell infiltration and activation and improve long-term tumor response. Aim 3. Determine if secondary boosts of oHSV IOT during imaging-identified timing windows of decreased T cell infiltration and activation can salvage therapeutic response. ImmunoPET imaging allows longitudinal quantification of underlying immunological kinetics during oncolytic herpes simplex virus (oHSV) immunotherapy (IOT) that will allow optimization of therapeutic regimens on a personalized basis.

项目摘要 该项目的总体目标是量化T细胞激活和渗透的时间动力学 在新型组合肿瘤内肿瘤疱疹单纯疱疹病毒（OHSV）免疫疗法中 胶质母细胞瘤（GBM）临床前模型中的分子免疫发射断层扫描（PET）成像。 新型靶向OHSV免疫疗法已显示可直接杀死GBM肿瘤细胞作为病毒 在内部复制和裂解裂解细胞恶化，但是了解的知识差距 免疫细胞的动力学会改变以及如何利用这些变化以提高治疗功效。作为 炎症和伪进展是免疫疗法诱导的肿瘤变化的关键特征， 标准成像方法无法提供可靠的响应评估，有时最多可能需要六个 几个月来通过肿瘤大小的临床变化揭示。高级定量成像策略可以提供 关于临床观察之前的生物学改变的空间和时间信息，下游变化 肿瘤大小。免疫成像可以分层进行免疫疗法和指导的患者的选择 组合疗法的时间和测序。我们有初步数据，表明有 OHSV治疗期间神经胶质瘤中CD8表达的差异反应，OHSV增加CD8 渗透，因为我们可以将这些变化与PET形象成像。此外，初步证据表明颗粒酶B 增加（通过GZP-PET衡量）与总体肿瘤反应有关。总体假设是宠物 分子成像可以引导靶向的IL-12和IL-18 OHSV，以增强治疗功效并延长生存率 在GBM的临床前模型中。有三个特定的目的可以回答这一假设：目标1。使用高级 具有生物学验证的GBM鼠模型中的分子免疫集，确定早期的T细胞动力学是否是 单独使用OHSV治疗后，或以OHSV表达IL-12和/或IL-的浸润和激活增加 18。我们将用[89ZR] -CD8-PET成像CD8+细胞和 用[68GA] -GZP-PET成像量化T细胞激活（晶圆酶B）中的纵向改变。目标2。使用 GBM鼠模型中的晚期分子免疫集，确定二级治疗（放射治疗， 或免疫调节性免疫检查点抑制剂）与OHSV IoT产品结合使用增加 中间任期T细胞浸润和激活并改善长期肿瘤反应。目标3。确定是否 在成像识别的定时窗口降低T细胞浸润和 激活可以挽救治疗反应。免疫集成像允许纵向定量 溶瘤疱疹病毒（OHSV）免疫疗法（IOT）的潜在免疫动力学 允许在个性化的基础上优化治疗方案。