Adoptive therapy using chimeric antigen receptor-modified T cells (CAR-T cells) is effective in hematologic but not epithelial malignancies, which cause the greatest mortality. In breast and lung cancer patients, CAR-T cells targeting the tumor-associated antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) infiltrate tumors poorly and become dysfunctional. To test strategies for enhancing efficacy, we adapted the Kras^LSL-G12D/+;p53^f/f autochthonous model of lung adenocarcinoma to express the CAR target ROR1. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently control tumor growth but infiltrate tumors poorly and lose function, similar to what is seen in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activates tumor macrophages to express T-cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improves CAR-T cell-mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic.

使用嵌合抗原受体修饰的 T 细胞（CAR-T 细胞）的过继治疗对血液系统恶性肿瘤有效，但对死亡率最高的上皮恶性肿瘤无效。在乳腺癌和肺癌患者中，靶向肿瘤相关抗原受体酪氨酸激酶样孤儿受体 1 (ROR1) 的 CAR-T 细胞难以浸润肿瘤并变得功能失调。为了测试提高功效的策略，我们调整了Kras ^LSL-G12D/+ ;p53 ^f/f表达CAR靶标ROR1的肺腺癌本土模型。小鼠 ROR1 CAR-T 细胞在用环磷酰胺 (Cy) 进行淋巴清除后转移，可暂时控制肿瘤生长，但肿瘤浸润性较差并失去功能，类似于在患者中看到的情况。在淋巴清除方案中添加奥沙利铂 (Ox) 可激活肿瘤巨噬细胞表达 T 细胞募集趋化因子，从而改善 CAR-T 细胞浸润、重塑肿瘤微环境并增加肿瘤对抗 PD-L1 的敏感性。Ox/Cy 和抗 PD-L1 的联合治疗协同提高了 CAR-T 细胞介导的肿瘤控制和存活率，为提高 CAR-T 细胞在临床上的疗效提供了策略。