肿瘤细胞治疗研究
英文原题：IL13RA2-integrated genetically engineered mouse model allows for CAR T cells targeting pediatric high-grade gliomas.
在表达与不表达 IL13RA2 的模型中均出现新发肿瘤，其发生时间无统计学差异（n = 33，38 天，p = 0.62）。
儿童高级别胶质瘤（pHGG）和儿童弥漫性中线胶质瘤（pDMG）是致命性疾病，目前缺乏持久有效的治愈方案。尽管靶向免疫疗法显示出希望，该领域仍缺乏能够详细研究相关过程的免疫功能完整动物模型。为此，研究者构建了免疫功能完整的pDMG和pHGG基因工程小鼠模型（GEMM），并纳入胶质瘤相关抗原白细胞介素13受体α2（IL13RA2）。研究在Nestin-Tva小鼠中利用RCAS-Tva递送系统，通过在新生小鼠中过表达PDGFB并敲除p53（p53 fl/fl）或同时敲除p53和PTEN（p53 fl/fl PTEN fl/fl），构建有或无IL13RA2表达的模型以诱导胶质瘤发生。无论是否表达IL13RA2，模型均形成原发肿瘤，发病时间无统计学差异（n=33，38天，p=0.62）。p53和PTEN双敲除肿瘤表现出更强侵袭性（n=12，31天）。肿瘤具有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；还表现出较高Ki-67指数、IL13RA2表达不一、CD11b⁺巨噬细胞比例较高和CD3⁺ T细胞比例较低。该模型适用于评估IL13RA2靶向免疫疗法。CAR-T细胞治疗产生显著应答，可延长小鼠生存期（治疗组46天，对照组28天；p<0.0001），并使25%的小鼠长期存活。该模型有助于临床前评估IL13RA2靶向疗法，并具有临床应用潜力。
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 fl/fl ) or both p53 and PTEN (p53 fl/fl PTEN fl/fl ), 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 fl/fl PTEN fl/fl 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.
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