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MyD88-mediated chimaeric antigen receptor macrophages suppress brain metastasis using target-specific phagocytosis
Shih-Ying Wu1,2, Abhishek Tyagi3, Kerui Wu3
1Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA. Shihying.Wu@advocatehealth.org.
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.
Insights
Engineered macrophages targeting mesothelin (MSLN) cross the blood-brain barrier (BBB) to treat brain metastases. This novel CAR-macrophage therapy (CARMA) reduced tumor growth and offers a promising new approach for brain cancer patients.
Area of Science:
- Oncology
- Immunotherapy
- Nanomedicine
Background:
- Brain metastases affect up to 30% of cancer patients, with limited treatment options due to the blood-brain barrier (BBB).
- Current therapies, including chemotherapy and immunotherapy, struggle to penetrate the BBB and effectively target brain tumors.
- Macrophages' natural ability to cross the BBB and phagocytose tumor cells presents a potential therapeutic avenue.
Purpose of the Study:
- To develop and evaluate a novel cell-based therapy for brain metastases.
- To engineer macrophages to specifically target mesothelin (MSLN)-expressing brain tumors.
- To assess the efficacy of these engineered macrophages in reducing brain metastasis growth.
Main Methods:
- Genetically engineered macrophages to express a mesothelin-targeting chimeric antigen receptor (CAR).
- Fused engineered macrophages with MyD88 to enhance immune signaling and BBB penetration, creating CAR-macrophages (CARMA).
- Evaluated CARMA's ability to cross the BBB and reduce brain metastasis in a humanized mouse model.
Main Results:
- Engineered CARMA successfully penetrated the blood-brain barrier (BBB) in a humanized mouse model.
- MSLN-CARMA demonstrated antigen-specific phagocytosis of tumor cells.
- CARMA exhibited a bystander effect, releasing TNF to eliminate surrounding tumor cells lacking the target antigen, reducing brain metastasis growth.
Conclusions:
- CARMA therapy shows promise for treating brain metastases by overcoming BBB limitations.
- The dual action of phagocytosis and bystander effect offers advantages over existing immunotherapies.
- MSLN-CARMA represents a potential new therapeutic strategy for patients with metastatic brain disease.
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