Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain.
Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain.
Clin Cancer Res. 2021 Mar 15;27(6):1807-1820. doi: 10.1158/1078-0432.CCR-20-3313. Epub 2020 Dec 29.
Atypical teratoid/rhabdoid tumors (AT/RT) and central nervous system primitive neuroectodermal tumors (CNS-PNET) are pediatric brain tumors with poor survival and life-long negative side effects. Here, the aim was to characterize the efficacy and safety of the oncolytic adenovirus, Delta-24-RGD, which selectively replicates in and kills tumor cells.
Delta-24-RGD determinants for infection and replication were evaluated in patient expression datasets. Viral replication and cytotoxicity were assessed in a battery of CNS-PNET and AT/RT cell lines. , efficacy was determined in different orthotopic mouse models, including early and established tumor models, a disseminated AT/RT lesion model, and immunocompetent humanized mouse models (hCD34-NSG-SGM3).
Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity [IC value below 1 plaque-forming unit (PFU)/cell] and the release of immunogenic markers. , a single intratumoral Delta-24-RGD injection (10 or 10 PFU) significantly increased survival and led to long-term survival in AT/RT and PNET models. Delta-24-RGD hindered the dissemination of AT/RTs and increased survival, leading to 70% of long-term survivors. Of relevance, viral administration to established tumor masses (30 days after engraftment) showed therapeutic benefit. In humanized immunocompetent models, Delta-24-RGD significantly extended the survival of mice bearing AT/RTs or PNETs (ranging from 11 to 27 days) and did not display any toxicity associated with inflammation. Immunophenotyping of Delta-24-RGD-treated tumors revealed increased CD8 T-cell infiltration.
Delta-24-RGD is a feasible therapeutic option for AT/RTs and CNS-PNETs. This work constitutes the basis for potential translation to the clinical setting.
非典型畸胎样/横纹肌样肿瘤（AT/RT）和中枢神经系统原始神经外胚层肿瘤（CNS-PNET）是儿科脑肿瘤，其生存率低，且存在终生的负面副作用。本研究旨在研究溶瘤腺病毒 Delta-24-RGD 的疗效和安全性，该病毒可选择性复制和杀伤肿瘤细胞。
在患者表达数据集评估 Delta-24-RGD 用于感染和复制的决定因素。在一系列 CNS-PNET 和 AT/RT 细胞系中评估病毒复制和细胞毒性。在不同的原位小鼠模型中，包括早期和已建立的肿瘤模型、播散性 AT/RT 病变模型和免疫活性人源化小鼠模型（hCD34-NSG-SGM3），确定疗效。
Delta-24-RGD 有效地感染和复制了所有测试的细胞系。此外，该病毒诱导了剂量依赖性细胞毒性（IC 值低于 1 噬菌斑形成单位（PFU）/细胞）和免疫原性标志物的释放。单次肿瘤内 Delta-24-RGD 注射（10 或 10 PFU）显著提高了生存率，并在 AT/RT 和 PNET 模型中导致长期存活。Delta-24-RGD 阻碍了 AT/RT 的播散并提高了生存率，导致 70%的长期幸存者。值得注意的是，在已建立的肿瘤肿块（植入后 30 天）中给予病毒治疗显示出治疗益处。在人源化免疫活性模型中，Delta-24-RGD 显著延长了携带 AT/RT 或 PNET 的小鼠的存活时间（范围为 11 至 27 天），且没有显示出任何与炎症相关的毒性。Delta-24-RGD 治疗的肿瘤的免疫表型分析显示 CD8 T 细胞浸润增加。
Delta-24-RGD 是治疗 AT/RT 和 CNS-PNET 的可行治疗选择。这项工作为潜在的临床转化奠定了基础。
