CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
经 NFAT 诱导型膜锚定 IL15/IL21 工程改造的 GPC2 靶向 CAR-T 细胞对神经母细胞瘤表现出增强的活性
英文原题：GPC2-Targeted CAR T Cells Engineered with NFAT-Inducible Membrane-Tethered IL15/IL21 Exhibit Enhanced Activity against Neuroblastoma.
查看英文原题
GPC2-Targeted CAR T Cells Engineered with NFAT-Inducible Membrane-Tethered IL15/IL21 Exhibit Enhanced Activity against Neuroblastoma.
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中文摘要
神经母细胞瘤是一种高度侵袭性的儿童实体瘤，预后较差。嵌合抗原受体（CAR）T细胞在神经母细胞瘤中显示出有限的疗效，在低肿瘤负荷患者中报告了最佳结局，这凸显了进一步优化CAR的必要性。解决高肿瘤负荷的一种方法是通过工程化改造使CAR-T 细胞释放或表达转基因细胞因子。
然而，其全身毒性仍然是一个重要的治疗挑战。在本研究中，我们评估了IL15和IL21增强的靶向glypican 2（GPC2）的CAR-T 细胞（GPC2-CAR-T 细胞）在靶向高负荷神经母细胞瘤中的疗效。评估了三种表达细胞因子的策略：组成型分泌（GPC2-CAR + sol.IL15.IL21）、组成型膜锚定表达（GPC2-CAR + teth.IL15.IL21）和NFAT诱导型膜锚定表达（GPC2-CAR + NFAT.IL15.IL21）。工程化GPC2-CAR-T 细胞在高神经母细胞瘤负荷异种移植模型中进行了体外和体内测试。
此外，使用单细胞RNA测序对肿瘤微环境中的效应细胞进行了分析。与对照GPC2-CAR-T 细胞相比，所有三种版本的GPC2-CAR-T 细胞在体外和体内均显著增强了对高神经母细胞瘤负荷的杀伤。接受GPC2-CAR + NFAT.IL15.IL21治疗的小鼠表现出显著较低的厌食相关发病率/死亡率。支持这些数据的是，肿瘤浸润的GPC2-CAR + NFAT.IL15.IL21在肿瘤消退后形成了免疫抑制性转录谱，从而导致治疗小鼠的生存期延长。相比之下，GPC2-CAR + teth.IL15.IL21尽管接近肿瘤清除，仍维持促炎性转录特征，导致高细胞因子血症和死亡。NFAT诱导的锚定IL15/IL21共表达增强了GPC2-CAR-T 细胞对抗高神经母细胞瘤负荷的功能，且在小鼠中耐受性可接受。需要进一步研究来验证这些发现。
展开英文摘要原文
Neuroblastoma is a highly aggressive childhood solid tumor with poor outcomes. Chimeric antigen receptor (CAR) T cells have shown limited efficacy in neuroblastoma, with the best outcomes reported in patients with a low tumor burden, highlighting the need for further CAR optimization. One approach to addressing the high tumor burden involves engineering CAR T cells to release or express transgenic cytokines.
However, its systemic toxicity remains an important therapeutic challenge. In this study, we evaluated the efficacy of IL15- and IL21-enhanced glypican 2 (GPC2)-targeted CAR T cells (GPC2-CAR T cells) in targeting high-burden neuroblastoma. Three strategies for expressing the cytokines were evaluated: constitutive secretion (GPC2-CAR + sol.
IL15. IL21), constitutive membrane-tethered expression (GPC2-CAR + teth. IL15. IL21), and NFAT-inducible membrane-tethered expression (GPC2-CAR + NFAT. IL15. IL21). Engineered GPC2-CAR T cells were tested in vitro and in vivo using high neuroblastoma burden xenograft models.
Additionally, single-cell RNA sequencing was used to profile the effector cells in the tumor microenvironment. All three versions of GPC2-CAR T cells significantly enhanced killing against a high neuroblastoma burden, both in vitro and in vivo, relative to control GPC2-CAR T cells. Mice treated with GPC2-CAR + NFAT. IL15. IL21 exhibited significantly lower anorexia-associated morbidity/mortality. Supporting these data, tumor-infiltrating GPC2-CAR + NFAT.
IL15. IL21 developed an immunosuppressive transcriptional profile upon tumor regression, leading to prolonged survival in treated mice. In contrast, GPC2-CAR + teth. IL15. IL21 maintained a proinflammatory transcriptional signature despite near tumor clearance, resulting in hypercytokinemia and death. NFAT-inducible co-expression of tethered IL15/IL21 enhanced GPC2-CAR T-cell function against a high neuroblastoma burden with acceptable tolerability in mice.
Further studies are required to validate these findings.
论文信息
- 作者
- Okada R、Reyes-González JM、Rodriguez C、Kondo T、Oh J、Sun M、Kelly MC、Zhang L
- 单位
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.United States
- 期刊
- Cancer immunology research2025 Sep 2
- 原文标识
- PubMed 40569285 · DOI 10.1158/2326-6066.CIR-24-0975
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