Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade

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 developed 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 reduced tumor burden, prolonged survival, remodeled the TME, increased intratumoral T cell and natural killer (NK) cell infiltration, and induced epitope spreading. CAR-M therapy protected against antigen-negative relapse in a T cell dependent fashion, confirming long-term anti-tumor immunity. In HER2+ solid tumors resistant to anti-PD1(aPD1) monotherapy, the combination of CAR-M and aPD1 significantly improved tumor growth control, survival, and remodeling of the TME. These results demonstrate synergy between CAR-M and T cell checkpoint blockade and provide a strategy to enhance response to aPD1 therapy for patients with non-responsive tumors. Overall design: HSCs and monocytes were differentiated into macrophages by treatment with either M-CSF or GM-CSF. Cells were either untransduced or Adf5f35 virally transduced HER2 Chimeric Antigen Receptor (CAR) macrophages. Untreated untransduced monocytes and hematopoietic stem cells were used as controls.

本团队此前已构建人源嵌合抗原受体巨噬细胞（CAR-M），并证实其可重定向巨噬细胞的抗肿瘤功能，在免疫缺陷异种移植模型中实现肿瘤控制。
本研究构建了临床相关的完全免疫健全同基因模型，用以评估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免疫检查点阻断敏感的潜力。
体内实验结果显示，抗HER2 CAR-M可显著降低肿瘤负荷、延长生存期、重塑肿瘤微环境（TME），增加瘤内T细胞与自然杀伤（NK）细胞浸润，并诱导表位扩散。
CAR-M治疗可通过T细胞依赖性方式预防抗原阴性复发，证实其可诱导长期抗肿瘤免疫。
在对抗PD1（aPD1）单药治疗耐药的HER2阳性实体瘤中，CAR-M与aPD1联合疗法可显著改善肿瘤生长控制效果、延长生存期，并重塑肿瘤微环境（TME）。
上述结果证实了CAR-M与T细胞免疫检查点阻断疗法的协同作用，为耐药肿瘤患者增强aPD1治疗应答提供了可行策略。
实验整体设计：通过巨噬细胞集落刺激因子（M-CSF）或粒细胞-巨噬细胞集落刺激因子（GM-CSF）处理，将造血干细胞（HSCs）与单核细胞分化为巨噬细胞。实验细胞分为未转导组，以及经Adf5f35病毒转导的HER2嵌合抗原受体（CAR）巨噬细胞组。以未处理的未转导单核细胞与造血干细胞作为对照。