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

项目总结 这个项目的首要目标是量化T细胞激活和渗透的时间动力学 在肿瘤内溶瘤性单纯疱疹病毒(OHSV)免疫治疗与晚期联合治疗期间 分子免疫正电子发射断层扫描在胶质母细胞瘤临床前模型中的应用。 新的靶向OHSV免疫疗法已被证明直接作为病毒选择性地杀死GBM肿瘤细胞 在恶性转化的细胞内复制和裂解，但在理解上存在知识鸿沟 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。AS 炎症和假性进展是免疫治疗诱导的肿瘤改变的关键特征， 标准的成像方法无法提供可靠的反应评估，这有时需要长达六次 几个月来通过临床肿瘤大小的变化揭示。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关于生物变化的空间和时间信息 在肿瘤大小上。免疫-PET成像可以对选择接受免疫治疗的患者进行分层并指导 组合疗法的时机和顺序。我们有初步数据显示有 OHSV治疗过程中胶质瘤中CD8表达的差异反应及OHSV增加CD8的作用 渗透，因为我们可以用PET来想象这些变化。此外，初步证据表明，颗粒酶B 增加(由GZP-PET测量)与总体肿瘤反应有关。最重要的假设是PET 分子成像可引导靶向IL-12和IL-18 OHSV提高治疗效果和延长生存期 在GBM的临床前模型中。有三个具体的目的来回答这个假设：目标1.使用高级 分子免疫PET在GBM小鼠模型中的生物学验证，确定早期T细胞动力学 单纯OHSV治疗或OHSV表达IL-12和/或IL-2后，细胞的浸润和活化增加 18.我们将用CD8+细胞和CD8+细胞的[89Zr]-CD8-PET成像来量化T细胞渗透的纵向变化 用[68Ga]-GZP-PET成像定量T细胞激活(颗粒酶B)的纵向变化。目标2.使用 先进的分子免疫PET在GBM小鼠模型中，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联合使用可增加 中期T细胞的浸润和活化，提高了肿瘤的远期疗效。目标3.确定是否 OHSV IOT在成像期间的二次增强-确定的T细胞浸润减少和 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)期间的潜在免疫学动力学 允许在个性化的基础上优化治疗方案。

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.