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.

项目概要 该项目的首要目标是量化 T 细胞激活和浸润的时间动力学 在新型联合瘤内溶瘤单纯疱疹病毒（oHSV）免疫治疗期间 胶质母细胞瘤（GBM）临床前模型中的分子免疫正电子发射断层扫描（PET）成像。 新型靶向 oHSV 免疫疗法已被证明可以直接杀死 GBM 肿瘤细胞，因为病毒选择性地杀死 GBM 肿瘤细胞 在恶性转化细胞内复制并裂解恶性转化细胞，但是在理解上存在知识差距 免疫细胞变化的动力学以及如何利用这些变化来提高治疗效果。作为 炎症和假性进展是免疫治疗引起的肿瘤变化的关键特征， 标准成像方法无法提供可靠的反应评估，有时可能需要多达六次 几个月才能通过肿瘤大小的临床变化来揭示。先进的定量成像策略可以提供 在临床观察到的下游变化之前生物变化的空间和时间信息 在肿瘤大小方面。免疫 PET 成像可以对寻求免疫治疗的患者进行分层选择并指导 组合疗法的时机和顺序。我们有初步数据显示，有 oHSV 治疗期间神经胶质瘤中 CD8 表达的差异反应以及 oHSV 增加 CD8 渗透，因为我们可以用 PET 对这些变化进行成像。此外，初步证据表明，颗粒酶 B 增加（通过 GZP-PET 测量）与总体肿瘤反应相关。总体假设是 PET 分子成像可以指导靶向 IL-12 和 IL-18 oHSV 以增强治疗效果并延长生存期 GBM 的临床前模型。回答这个假设有三个具体目标： 目标 1. 使用先进的 GBM 小鼠模型中的分子免疫 PET 进行生物学验证，确定早期 T 细胞动力学是否 单独治疗 oHSV 或使用表达 IL-12 和/或 IL-12 的 oHSV 治疗后，浸润和激活会增加。 18. 我们将通过 CD8+ 细胞的 [89Zr]-CD8-PET 成像来量化 T 细胞浸润的纵向变化， 使用 [68Ga]-GZP-PET 成像量化 T 细胞激活（颗粒酶 B）的纵向变化。目标 2. 使用 GBM 小鼠模型中的先进分子免疫 PET，确定是否需要二次治疗（放射治疗、 或免疫调节性免疫检查点抑制剂）与 oHSV IOT 联合使用产生增加 中期 T 细胞浸润和激活，改善长期肿瘤反应。目标 3. 确定是否 在成像识别的 T 细胞浸润减少的时间窗口期间，oHSV IOT 的二次增强 激活可以挽救治疗反应。免疫PET成像允许纵向量化 溶瘤单纯疱疹病毒 (oHSV) 免疫治疗 (IOT) 期间的潜在免疫动力学 允许在个性化的基础上优化治疗方案。