Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China.
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China.
J Natl Cancer Inst. 2024 Mar 7;116(3):389-400. doi: 10.1093/jnci/djad226.
Poliovirus receptor interacts with 3 receptors: T-cell immunoglobulin immunoreceptor tyrosine-based inhibitory motif, CD96, and DNAX accessory molecule 1, which are predominantly expressed on T cells and natural killer (NK) cells. Many solid tumors, including IDH wild-type glioblastoma, have been reported to overexpress poliovirus receptor, and this overexpression is associated with poor prognosis. However, there are no preclinical or clinical trials investigating the use of cell-based immunotherapies targeting poliovirus receptor in IDH wild-type glioblastoma.
We analyzed poliovirus receptor expression in transcriptome sequencing databases and specimens from IDH wild-type glioblastoma patients. We developed poliovirus receptor targeting chimeric antigen receptor T cells using lentivirus. The antitumor activity of chimeric antigen receptor T cells was demonstrated in patient-derived glioma stem cells, intracranial and subcutaneous mouse xenograft models.
We verified poliovirus receptor expression in primary glioma stem cells, surgical specimens from IDH wild-type glioblastoma patients, and organoids. Accordingly, we developed poliovirus receptor-based second-generation chimeric antigen receptor T cells. The antitumor activity of chimeric antigen receptor T cells was demonstrated in glioma stem cells and xenograft models. Tumor recurrence occurred in intracranial xenograft models because of antigen loss. The combinational therapy of tyrosine-based inhibitory motif extracellular domain-based chimeric antigen receptor T cells and NK-92 cells markedly suppressed tumor recurrence and prolonged survival.
Poliovirus receptor-based chimeric antigen receptor T cells were capable of killing glioma stem cells and suppressing tumor recurrence when combined with NK-92 cells.
脊髓灰质炎病毒受体与 3 种受体相互作用：T 细胞免疫球蛋白免疫受体酪氨酸基抑制基序、CD96 和 DNAX 辅助分子 1，这些受体主要表达于 T 细胞和自然杀伤（NK）细胞上。许多实体瘤，包括 IDH 野生型脑胶质瘤，已被报道过过度表达脊髓灰质炎病毒受体，这种过表达与预后不良有关。然而，目前尚无临床试验研究针对 IDH 野生型脑胶质瘤中使用靶向脊髓灰质炎病毒受体的细胞免疫疗法。
我们分析了 IDH 野生型脑胶质瘤患者的转录组测序数据库和标本中的脊髓灰质炎病毒受体表达情况。我们使用慢病毒开发了靶向脊髓灰质炎病毒受体的嵌合抗原受体 T 细胞。嵌合抗原受体 T 细胞在患者来源的脑胶质瘤干细胞、颅内和皮下小鼠异种移植模型中的抗肿瘤活性。
我们验证了原发性脑胶质瘤干细胞、IDH 野生型脑胶质瘤患者的手术标本和类器官中脊髓灰质炎病毒受体的表达。因此，我们开发了基于脊髓灰质炎病毒受体的第二代嵌合抗原受体 T 细胞。嵌合抗原受体 T 细胞在脑胶质瘤干细胞和异种移植模型中的抗肿瘤活性得到了证实。由于抗原丢失，颅内异种移植模型中发生了肿瘤复发。基于酪氨酸基抑制基序的嵌合抗原受体 T 细胞和 NK-92 细胞的联合治疗显著抑制了肿瘤复发并延长了生存期。
基于脊髓灰质炎病毒受体的嵌合抗原受体 T 细胞在与 NK-92 细胞联合使用时能够杀伤脑胶质瘤干细胞并抑制肿瘤复发。
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