肿瘤细胞治疗研究
英文原题：Engineering Interferon-γ-Enhanced Chimeric Antigen Receptor Macrophages via Lipid-Assisted Polymeric Nanoparticles for Cancer Immunotherapy.
目的 To develop an efficient strategy for in vivo engineering of M1-like CAR-Ms for cancer therapy. 方法 We designed a lentiviral vector encoding a CAR targeting BCMA and a cytokine cassette. Macrophages were transduced and polarized to M1-like phenotype. In vitro and in vivo assays were performed to evaluate the antitumor activity. 结果 The engineered M1-like CAR-Ms showed enhanced phagocytosis and cytokine secretion. In mouse models, the CAR-Ms significantly inhibited tumor growth and prolonged survival. 结论 In vivo engineering of M1-like CAR-Ms represents a promising approach for cancer immunotherapy.
嵌合抗原受体巨噬细胞（CAR-Ms）因其肿瘤穿透特性和抗原特异性吞噬作用，在实体瘤治疗中具有广阔前景。然而，目前的CAR-M疗法受限于巨噬细胞体外增殖能力低以及工程化过程的复杂性。在体内生成CAR-Ms可以克服这些挑战，但仍面临由免疫抑制性肿瘤微环境极化的M2样促肿瘤表型问题。在此，我们设计了巨噬细胞优先的离子化阳离子脂质辅助聚合物纳米颗粒（iCLANs），共递送编码干扰素-γ（IFN-γ）和CAR分子的mRNA，记为iCLANmCAR+mIFN-γ，从而实现在体内工程化具有持续M1样表型的CAR-Ms。iCLANmCAR+mIFN-γ可在肿瘤相关巨噬细胞中共表达IFN-γ和CAR，从而产生能够维持抗肿瘤表型、以抗原特异性方式有效吞噬肿瘤细胞的CAR-Ms。在EGFRvIII+乳腺肿瘤和CD19+ B细胞淋巴瘤模型中静脉注射iCLANmCAR+mIFN-γ，可直接在肿瘤内生成EGFRvIII CAR-Ms或CD19 CAR-Ms，导致显著的肿瘤生长抑制和免疫抑制性肿瘤微环境的重塑。本研究为体内工程化M1样CAR-Ms用于癌症治疗提供了一种高效策略。
Chimeric antigen receptor macrophages (CAR-Ms) are promising in solid tumor therapy due to their tumor-penetrating property and antigen-specific phagocytosis. However, current CAR-M therapy is limited by the low ex vivo proliferation of macrophages and the complexity of the engineering process. Generating CAR-Ms in vivo can overcome these challenges but still faces an M2-like pro-tumor phenotype polarized by immunosuppressive tumor microenvironment. Herein, we devise macrophage-preferential ionizable cationic lipid-assisted polymeric nanoparticles (iCLANs) to co-deliver mRNAs encoding interferon-γ (IFN-γ) and a CAR molecule, denoted as iCLANmCAR+mIFN-γ, enabling in vivo engineering of CAR-Ms with a sustained M1-like phenotype. iCLANmCAR+mIFN-γ can coexpress IFN-γ and CAR in tumor-associated macrophages, thereby producing CAR-Ms capable of maintaining antitumor phenotype to effectively engulf tumor cells in an antigen-specific manner. Intravenous injection of iCLANmCAR+mIFN-γ in EGFRvIII+ breast tumor and CD19+ B-cell lymphoma models directly generates EGFRvIII CAR-Ms or CD19 CAR-Ms within tumors, resulting in significant tumor growth inhibition and remodeling of the immunosuppressive tumor microenvironment. This study provides an efficient strategy for in vivo engineering of M1-like CAR-Ms for cancer therapy.
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