肿瘤细胞治疗研究
英文原题：A radiopharmaceutical enhances CAR T cells against radio-sensitive and radio-resistant neuroblastoma by tumor sensitization and TME remodeling.
嵌合抗原受体（CAR）T 细胞疗法对神经母细胞瘤（NB）等实体瘤的疗效有限。
嵌合抗原受体（CAR）T细胞疗法治疗神经母细胞瘤（NB）等实体瘤的疗效有限。关键障碍包括肿瘤负荷大及存在免疫抑制性肿瘤微环境（TME）。我们采用靶向放射性药物治疗（RPT）[⁶⁷Cu]Cu-LLP2A，发现其通过不同机制增强放射敏感和放射耐受型NB模型中的CAR-T抗肿瘤活性。在放射敏感型NB中，RPT可直接杀伤肿瘤，同时通过促免疫通路，尤其TNF-α通路，增强CAR-T疗效，进而旁分泌性活化T细胞。在放射耐受型NB中，RPT可重塑TME中的髓系细胞区室，增加细胞毒性CD8⁺GZMB⁺及CD4⁺GZMB⁺ CAR-T细胞免疫生态位形成。尽管单独使用任一种治疗均无法有效治疗NB，但靶向VLA-4的RPT联合GD2或B7-H3 CAR-T细胞可增强抗肿瘤疗效，在临床前NB模型中导致明显肿瘤消退。
Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors such as neuroblastoma (NB). Key obstacles include extensive tumor burden and the presence of an immunosuppressive tumor microenvironment (TME). We employ targeted radiopharmaceutical therapy (RPT) using [ 67 Cu]Cu-LLP2A and show that it potentiated the anti-tumor activity of CAR T cells in radio-sensitive and radio-resistant NB models via distinct mechanisms. In radio-sensitive NB, RPT is directly tumoricidal while also enhancing CAR T cell efficacy through pro-immune pathways, most notably via the TNF- pathway, leading to paracrine activation of T cells. In radio-resistant NB, RPT improves CAR T cells by remodeling the myeloid compartment in the TME and increasing the formation of immunological niches of cytotoxic CD8 + GZMB + and CD4 + GZMB + CAR T cells. While neither treatment modality alone can effectively treat NB, the combination of VLA-4-targeted RPT and GD2 or B7-H3 CAR T cells augments anti-tumor efficacy, resulting in marked tumor regression in preclinical NB models.
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