Human chimeric antigen receptor macrophages for cancer immunotherapy.,Nature Biotechnology

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Human chimeric antigen receptor macrophages for cancer immunotherapy.
Nature Biotechnology ( IF 33.1 ) Pub Date : 2020-03-23 , DOI: 10.1038/s41587-020-0462-y
Michael Klichinsky _{1,

2,

3} , Marco Ruella _{1,

4} , Olga Shestova ₁ , Xueqing Maggie Lu _{1,

5} , Andrew Best _{1,

3} , Martha Zeeman ₃ , Maggie Schmierer ₃ , Konrad Gabrusiewicz ₃ , Nicholas R Anderson ₃ , Nicholas E Petty ₁ , Katherine D Cummins ₁ , Feng Shen ₁ , Xinhe Shan ₁ , Kimberly Veliz ₁ , Kristin Blouch ₁ , Yumi Yashiro-Ohtani ₃ , Saad S Kenderian _{1,

6} , Miriam Y Kim _{1,

7} , Roddy S O'Connor ₁ , Stephen R Wallace ₁ , Miroslaw S Kozlowski ₁ , Dylan M Marchione _{2,

8} , Maksim Shestov ₁ , Benjamin A Garcia ₈ , Carl H June _{1,

2,

9} , Saar Gill _{1,

2,

4}

Affiliation

Chimeric antigen receptor (CAR) T cell therapy has shown promise in hematologic malignancies, but its application to solid tumors has been challenging1-4. Given the unique effector functions of macrophages and their capacity to penetrate tumors5, we genetically engineered human macrophages with CARs to direct their phagocytic activity against tumors. We found that a chimeric adenoviral vector overcame the inherent resistance of primary human macrophages to genetic manipulation and imparted a sustained pro-inflammatory (M1) phenotype. CAR macrophages (CAR-Ms) demonstrated antigen-specific phagocytosis and tumor clearance in vitro. In two solid tumor xenograft mouse models, a single infusion of human CAR-Ms decreased tumor burden and prolonged overall survival. Characterization of CAR-M activity showed that CAR-Ms expressed pro-inflammatory cytokines and chemokines, converted bystander M2 macrophages to M1, upregulated antigen presentation machinery, recruited and presented antigen to T cells and resisted the effects of immunosuppressive cytokines. In humanized mouse models, CAR-Ms were further shown to induce a pro-inflammatory tumor microenvironment and boost anti-tumor T cell activity.

中文翻译：

用于癌症免疫治疗的人类嵌合抗原受体巨噬细胞。

嵌合抗原受体 (CAR) T 细胞疗法已在血液系统恶性肿瘤中显示出前景，但其在实体瘤中的应用一直具有挑战性 1-4。鉴于巨噬细胞独特的效应功能及其穿透肿瘤的能力，我们用 CAR 对人类巨噬细胞进行基因工程改造，以指导其对肿瘤的吞噬活性。我们发现嵌合腺病毒载体克服了原代人类巨噬细胞对基因操作的固有抵抗力，并赋予了持续的促炎 (M1) 表型。CAR巨噬细胞（CAR-Ms）在体外表现出抗原特异性吞噬作用和肿瘤清除作用。在两种实体瘤异种移植小鼠模型中，单次输注人类 CAR-M 可降低肿瘤负荷并延长总生存期。CAR-M活性的表征表明，CAR-Ms表达促炎细胞因子和趋化因子，将旁观者M2巨噬细胞转化为M1，上调抗原呈递机制，向T细胞募集和呈递抗原，并抵抗免疫抑制细胞因子的作用。在人源化小鼠模型中，CAR-Ms 被进一步证明可诱导促炎性肿瘤微环境并增强抗肿瘤 T 细胞活性。

更新日期：2020-04-24

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