Seblani M, Zannikou M, Duffy J T, Joshi T, Levine R N, Thakur A, Puigdelloses-Vallcorba M, Horbinski C M, Miska J, Hambardzumyan D, Becher O J, Balyasnikova Irina V
Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, 303 E. Superior St. Room 6-520, Chicago, IL, 60611, USA.
Acta Neuropathol Commun. 2025 Apr 2;13(1):69. doi: 10.1186/s40478-025-01991-4.
Pediatric high-grade gliomas (pHGG) and pediatric diffuse midline gliomas (pDMG) are devastating diseases without durable and curative options. Although targeted immunotherapy has shown promise, the field lacks immunocompetent animal models to study these processes in detail. To achieve this, we developed a fully immunocompetent, genetically engineered mouse model (GEMM) for pDMG and pHGG that incorporates the glioma-associated antigen, interleukin 13 receptor alpha 2 (IL13RA2). Utilizing the RCAS-Tva delivery system in Nestin-Tva mice, we induced gliomagenesis by overexpressing PDGFB and deleting p53 (p53) or both p53 and PTEN (p53 PTEN), with or without IL13RA2 in neonatal mice. De novo tumors developed in models with and without IL13RA2, showing no statistical difference in onset (n = 33, 38 days, p = 0.62). The p53 PTEN tumors displayed more aggressive characteristics (n = 12, 31 days). Tumors exhibited features typical of high-grade glioma, including infiltration, pseudopalisading necrosis, and microvascular proliferation. They also showed a high Ki-67 index, variable IL13RA2 expression, a high frequency of CD11b + macrophages, and a low proportion of CD3 + T cells. The model proved effective for evaluating IL13RA2-targeted immunotherapies, with a significant response to CAR T-cell treatment that extended survival (46 days vs. 28 days control; p < 0.0001) and achieved 25% long-term survival in mice. This model facilitates the preclinical assessment of IL13RA2-directed therapies and holds potential for clinical application.
小儿高级别胶质瘤（pHGG）和小儿弥漫性中线胶质瘤（pDMG）是极具破坏性的疾病，目前尚无持久有效的治愈方案。尽管靶向免疫疗法已显示出前景，但该领域缺乏具有免疫活性的动物模型来详细研究这些过程。为实现这一目标，我们开发了一种用于pDMG和pHGG的具有完全免疫活性的基因工程小鼠模型（GEMM），该模型整合了胶质瘤相关抗原白细胞介素13受体α2（IL13RA2）。利用Nestin-Tva小鼠中的RCAS-Tva递送系统，我们在新生小鼠中通过过表达血小板衍生生长因子B（PDGFB）并缺失p53（p53）或同时缺失p53和磷酸酶及张力蛋白同源物（PTEN）（p53 PTEN）来诱导胶质瘤发生，同时伴有或不伴有IL13RA2。在有和没有IL13RA2的模型中均出现了新生肿瘤，其发病时间无统计学差异（n = 33，38天，p = 0.62）。p53 PTEN肿瘤表现出更具侵袭性的特征（n = 12，31天）。肿瘤表现出高级别胶质瘤的典型特征，包括浸润、假栅栏状坏死和微血管增生。它们还显示出高Ki-67指数、可变的IL13RA2表达、高频率的CD11b +巨噬细胞以及低比例的CD3 + T细胞。该模型被证明对评估靶向IL13RA2的免疫疗法有效，对嵌合抗原受体（CAR）T细胞治疗有显著反应，可延长生存期（46天对28天对照；p < 0.0001），并使小鼠的长期生存率达到25%。该模型有助于对靶向IL13RA2的疗法进行临床前评估，并具有临床应用潜力。
