Engineering macrophages for effective and safe targeting of CD47 cancer cells in the tumor microenvironment

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Tumor-associated macrophages (TAMs) are crucial myeloid cells within the tumor microenvironment (TME).
• TAMs can either promote or restrict anti-tumor immunity through various mechanisms, including inhibitory receptor expression.
• The recruitment of TAMs into tumors makes them promising candidates for cell-based therapies.

Purpose of the Study:

• To engineer macrophages for enhanced anti-tumor activity within the TME.
• To overcome inhibitory signals, such as signal regulatory protein alpha (SIRPα), that cancer cells use to evade immune responses.
• To evaluate the therapeutic potential of engineered macrophages in preclinical cancer models.

Main Methods:

• Development of pArg1-CD47 CAR-Mφ, utilizing the Arg1 promoter for TME-specific activation.
• Testing the efficacy of CAR-Mφ in preclinical murine models of breast and gastric cancer.
• Assessing tumor regression and toxicity, particularly towards erythrocytes.

Main Results:

• pArg1-CD47 CAR-Mφ demonstrated TME-specific cytotoxicity, overcoming SIRPα inhibition against CD47+ cancer cells.
• Significant regression of established tumors was observed in breast and gastric cancer models.
• The engineered macrophage therapy exhibited minimal toxicity to erythrocytes.

Conclusions:

• Macrophage engineering holds significant therapeutic potential for treating solid tumors.
• pArg1-CD47 CAR-Mφ represents a promising strategy for myeloid cell-based cancer therapy.
• Further research is needed to translate these findings from preclinical models to human therapies, ensuring a safe and effective profile.