肿瘤细胞治疗研究
英文原题：Multiplex gene-editing strategy to engineer allogeneic EGFR-targeting CAR T-cells with improved efficacy against solid tumors.
嵌合抗原受体（CAR）T细胞已在血液系统癌症患者中诱导出显著的临床反应。
嵌合抗原受体（CAR）T细胞已在血液系统恶性肿瘤患者中诱导出显著的临床反应。然而，针对实体瘤的CAR T细胞疗法尚未取得类似结果，因为肿瘤微环境中的免疫抑制屏障会削弱抗肿瘤活性。在此，我们描述了一种多管齐下的方法，利用腺嘌呤碱基编辑器和CRISPR-Cas12b核酸酶，工程化改造同种异体CAR T细胞，使其对生化（缺氧-腺苷能）和免疫（PD-L1和TGF-）抑制信号均具有抗性。由此产生的靶向EGFR的CAR T细胞产品包含六种基因编辑的组合，旨在逃避同种异体排斥（B2M、CIITA）、预防移植物抗宿主病（CD3E），并克服皮下生长的EGFR+人肺肿瘤异种移植模型实体瘤微环境中的生化（ADORA2A）和免疫（PDCD1、TGFBR2）屏障。这种组合式基因破坏增强了CAR T细胞的效应功能和抗肿瘤疗效，从而在异种移植和人源化小鼠实体瘤模型中改善了肿瘤清除和生存。我们的策略赋予CAR T细胞对多种临床相关抑制信号通路的抗性，这些通路在缺氧肿瘤区域被放大，并可能提高CAR T细胞针对实体瘤的治疗潜力。
Chimeric Antigen Receptor (CAR) T cells have induced remarkable clinical responses in patients with hematological cancers. However, CAR T-cell therapies against solid tumors have not elicited similar outcomes since immunosuppressive barriers in the tumor microenvironment attenuate anti-tumor activity. Here, we describe a multifaceted approach to engineer allogeneic CAR T-cells resistant to both biochemical (hypoxia-adenosinergic) and immunological (PD-L1 and TGF- ) inhibitory signaling using an adenine base editor and a CRISPR-Cas12b nuclease. The resulting EGFR-targeting CAR T-cell product comprised a combination of six gene edits designed to evade allorejection (B2M, CIITA), prevent graft-versus-host disease (CD3E) and overcome biochemical (ADORA2A) and immunological (PDCD1, TGFBR2) barriers in solid tumor microenvironment of subcutaneously grown EGFR + human lung tumor xenografts. This combinatorial genetic disruption enhances CAR T cell effector function and anti-tumor efficacy leading to improved tumor elimination and survival in xenograft and humanized mouse solid tumor models. Our strategy confers CAR T cells resistance to multiple clinically relevant inhibitory signaling pathways that are amplified in hypoxic tumor areas and may improve the therapeutic potential of CAR T-cells against solid tumors.
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