肿瘤细胞治疗研究
英文原题：Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade in pre-clinical models.
这些结果证明了CAR-M与T细胞检查点阻断之间的协同作用，并提供了一种可能增强对aPD1治疗无响应肿瘤患者应答的策略。
我们之前开发了人类CAR巨噬细胞（CAR-M），并证明在免疫缺陷异种移植模型中，重定向巨噬细胞的抗肿瘤功能可导致肿瘤控制。在此，我们开发了临床相关的、完全免疫健全的同系模型，以评估CAR-M重塑肿瘤微环境（TME）、诱导T细胞抗肿瘤免疫以及使实体瘤对PD1/PDL1检查点抑制敏感的潜力。在体内，抗HER2 CAR-M显著降低肿瘤负荷、延长生存期、重塑TME、增加瘤内T细胞和自然杀伤（NK）细胞浸润，并诱导抗原扩散。CAR-M治疗以T细胞依赖的方式防止抗原阴性复发，证实了长期抗肿瘤免疫。在对anti-PD1（aPD1）单药治疗敏感性有限的HER2+实体瘤中，CAR-M与aPD1的联合在临床前模型中显著改善了肿瘤生长控制、生存期和TME重塑。这些结果证明了CAR-M与T细胞检查点阻断之间的协同作用，并提供了一种可能增强对aPD1治疗无应答肿瘤患者应答的策略。
We previously developed human CAR macrophages (CAR-M) and demonstrated redirection of macrophage anti-tumor function leading to tumor control in immunodeficient xenograft models. Here, we develop clinically relevant fully immunocompetent syngeneic models to evaluate the potential for CAR-M to remodel the tumor microenvironment (TME), induce T cell anti-tumor immunity, and sensitize solid tumors to PD1/PDL1 checkpoint inhibition. In vivo, anti-HER2 CAR-M significantly reduce tumor burden, prolong survival, remodel the TME, increase intratumoral T cell and natural killer (NK) cell infiltration, and induce antigen spreading. CAR-M therapy protects against antigen-negative relapses in a T cell dependent fashion, confirming long-term anti-tumor immunity. In HER2+ solid tumors with limited sensitivity to anti-PD1 (aPD1) monotherapy, the combination of CAR-M and aPD1 significantly improves tumor growth control, survival, and remodeling of the TME in pre-clinical models. These results demonstrate synergy between CAR-M and T cell checkpoint blockade and provide a strategy to potentially enhance response to aPD1 therapy for patients with non-responsive tumors.
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