MyD88-mediated chimaeric antigen receptor macrophages suppress brain metastasis using target-specific phagocytosis

Abstract

Metastatic brain disease occurs in up to 30% of patients with lung, melanoma and breast cancers, and the median survival time remains less than a year. Treating these patients is a challenge because surgical approaches are limited and most chemotherapeutic drugs and immunotherapies are ineffective at crossing the blood-brain barrier (BBB). Given the unique abilities of macrophages to cross the BBB and exert their phagocytic function on tumour cells, we genetically engineer macrophages that express a chimaeric antigen receptor (CAR) targeting mesothelin (MSLN). To specifically target metastatic brain tumours, we fused the cells with the immune signalling molecule MyD88. This chimaeric antigen receptor macrophage (CARMA) penetrates the BBB and decreases brain metastasis growth in a humanized mouse model. MSLN-CARMA shows antigen-specific phagocytosis activity against tumour cells and exhibits a bystander effect by releasing TNF to act on surrounding tumour cells lacking the tumour antigen. These features of CARMA represent advantages over other immune therapies and CARMA may serve as a promising therapeutic tool for the treatment of brain metastasis.