肿瘤细胞治疗研究
英文原题：CD47 antibody-armed oncolytic adenovirus promotes chimeric antigen receptor macrophage phagocytosis and antitumor immunity.
CAR-Ms 联合 oAd-CD47 的治疗策略为实体瘤的个体化靶向治疗提供了一种有前景、新颖且有效的治疗方法。
背景：CAR-T 在血液系统恶性肿瘤中取得成功，但治疗实体瘤仍面临挑战。巨噬细胞具有独特的吞噬功能，可能是有效治疗靶点，因此已催生多种治疗策略。本研究旨在开发有效的实体瘤免疫治疗策略，将靶向 PD-L1 的 CAR 巨噬细胞（CAR-M）与装载抗 CD47 抗体的溶瘤腺病毒（oAd-CD47）联合使用。方法：研究者使用腺病毒载体构建靶向 PD-L1 并表达 IFN-γ 的 CAR-M，在体外检测其吞噬能力和表型，并在两种免疫原性不同的小鼠肿瘤模型中评估体内抗肿瘤疗效。随后研究 CAR-M 与 oAd-CD47 的协同抗肿瘤作用及其机制。结果：CAR-M 吞噬能力增强，并呈促炎性 M1 表型。在具有高免疫原性的 CT26 结肠癌小鼠模型中，CAR-M 显著降低肿瘤负荷并延长总生存期。与 CAR-M 或 oAd-CD47 单药相比，联合治疗（C + o）在 CT26、B16 黑色素瘤及 ID8 腹膜转移模型中均具有更优抗肿瘤疗效。值得注意的是，C + o 治疗增强肿瘤相关巨噬细胞（TAM）的吞噬作用，并减少抑制性免疫细胞亚群，从而增强适应性抗肿瘤 T 细胞免疫和新抗原特异性 T 细胞免疫。此外，C + o 的协同抗肿瘤作用依赖 CD8⁺ T 细胞。结论：CAR-M 联合 oAd-CD47 为实体瘤个体化靶向治疗提供了一种有前景、新颖且有效的方法。
BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has shown success in hematologic malignancies but has encountered challenges in solid tumors. Macrophages, being a potentially effective therapeutic target, have led to the development of several therapeutic strategies due to their unique phagocytic function. This study aimed to develop an effective solid tumor immunotherapy strategy by combining CAR macrophages (CAR-Ms) targeting PD-L1 with CD47 antibody-armed oncolytic adenovirus (oAd-CD47). METHODS: In this study, an adenoviral vector was employed to construct CAR-Ms that target PD-L1 and express IFN- . The phagocytic capacity and phenotype of CAR-Ms were tested in vitro. Two mouse tumor models with different immunogenicity were utilized to investigate the anti-tumor efficacy of CAR-Ms in vivo. Subsequently, the synergistic anti-tumor effects of CAR-M and oAd-CD47 and their underlying mechanisms were explored. RESULTS: CAR-Ms exhibited enhanced phagocytic capacity and proinflammatory (M1) phenotype. These CAR-Ms significantly reduced tumor burden and extended overall survival in mice bearing CT26 colon cancer, a model characterized by high immunogenicity. Compared with CAR-Ms and oAd-CD47 monotherapy, this combination therapy (C + o) achieved superior antitumor efficacy in the CT26 and B16 melanoma mouse models, as well as in the ID8 peritoneal metastasis model. Notably, C + o treatment enhanced tumor-associated macrophage (TAM) phagocytosis and reduced the population of inhibitory immune cell subsets, thereby resulting in enhanced adaptive antitumor T-cell and neoantigen-specific T-cell immunity. Additionally, the synergistic antitumor effect of C + o was dependent on CD8 + T cells. CONCLUSION: The treatment strategy of CAR-Ms combined with oAd-CD47 provides a promising, novel and effective treatment method for individualized targeted therapy of solid tumors. [Image: see text]
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