肿瘤细胞治疗研究
英文原题：Low-dose radiation by radiopharmaceutical therapy enhances GD2 TRAC-CAR T cell efficacy in localized neuroblastoma.
嵌合抗原受体（CAR）T 细胞对包括神经母细胞瘤在内的实体瘤疗效有限。
嵌合抗原受体（CAR）T细胞治疗神经母细胞瘤等实体瘤的疗效有限。本研究评估放射性药物治疗（RPT）给予的低剂量辐射（已知可增强免疫检查点抑制剂疗效）能否与CRISPR编辑的GD2 TRAC缺失CAR-T细胞协同改善神经母细胞瘤治疗结局。我们发现，在局限性神经母细胞瘤模型中，先给予177Lu-NM600（一种烷基磷脂模拟物RPT药物）低剂量辐射，9天后再给予GD2 TRAC缺失CAR-T细胞，可使肿瘤完全消退。在输注GD2 TRAC缺失CAR-T细胞前照射神经母细胞瘤，可增强CAR-T细胞释放穿孔素、颗粒酶B、肿瘤坏死因子和白细胞介素7，同时抑制转化生长因子β1。RPT低剂量辐射会上调神经母细胞瘤细胞Fas死亡受体，可能使其能够发生CAR非依赖性杀伤。这提示低剂量RPT可增强CAR-T细胞对实体瘤的有限疗效。但针对不同患者和RPT药物，可能需要优化辐射剂量和时机，以适应肿瘤放射敏感性及剂量学差异。
Chimeric antigen receptor (CAR) T cells have limited efficacy against solid tumors including neuroblastoma. Here, we evaluated whether low-dose radiation delivered by radiopharmaceutical therapy (RPT), known to potentiate immune checkpoint inhibitors, can synergize with CRISPR-edited GD2 TRAC- CAR T cells to improve outcomes in neuroblastoma. We found that in the localized model of neuroblastoma, low-dose radiation delivered by 177 Lu-NM600, an alkylphosphocholine mimetic RPT agent, followed 9 days later by GD2 TRAC- CAR T cells led to complete tumor regression. Irradiation of neuroblastoma before GD2 TRAC- CAR T cells enhanced the release by CAR T cells of perforin, granzyme B, tumor necrosis factor- , and interleukin-7 while abrogating transforming growth factor- 1. Low-dose RPT up-regulated the death receptor Fas on neuroblastoma, potentially enabling CAR-independent killing. This suggests that low-dose RPT can enhance suboptimal CAR T cell efficacy against solid tumors. However, optimization of radiation dose and timing may be needed for each patient and RPT agent to account for varied tumor radiosensitivity and dosimetry.
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