Macrophages account for approximately 50% of the total tumor volume and are often one of the first cells to be taken up by solid tumors, and can also selectively kill cancer cells through phagocytosis. Macrophage therapy, as an emerging cellular therapy, is able to treat diseases through the immunomodulatory and anti-tumor activity of macrophages.

Here, Creative Biolabs presents recent advances in the development of CAR-M immunotherapies using macrophage engineering platforms.

Mechanism of Action of CAR-M

CAR-T cell therapy has gained significant attention and success in treating certain types of blood cancer. CAR-macrophage therapy takes a different approach by modifying macrophages, which is to enhance the macrophages' ability to recognize and destroy cancer cells.

Fig.1 The construct of CAR and CAR-engineered macrophage.¹

• Similar to CAR-T cell therapy, CAR-macrophage therapy involves genetic modification of the patient's own macrophages. This modification introduces a CAR that is designed to target specific antigens present on the surface of cancer cells.
• Once modified, the CAR-equipped macrophages are better equipped to recognize and bind to cancer cells. This recognition triggers the macrophages to engulf and destroy the cancer cells.

Advantages of CAR-M

Solid tumors are usually isolated in a dense fibrotic mass and hypoxic, immunosuppressive environment, a microenvironment that may adversely affect CAR-T cell activity and infiltration, making it difficult for CAR-T cells to effectively enter and function in tumor tissue.

Compared with CAR-T cell therapy, CAR-M has shown great advantages in the treatment of solid tumors.

• Microenvironmental adaptation: As macrophages are immune cells naturally present in the microenvironment of solid tumors, CAR-M cells have better microenvironmental adaptability and are able to traverse tumor tissues and function more easily.
• Phagocytosis: Macrophages have a powerful phagocytosis function and are able to ingest and digest tumor cells, thus killing them directly.
• Immunomodulation: Macrophages also have immunomodulation function, which can regulate the inflammatory response and immune response in the tumor microenvironment, and help to improve the suppression of immune cells by the tumor microenvironment.
• Long-term effects: Macrophages have a long survival time in vivo, which makes CAR-M cells potentially able to produce longer-lasting anti-tumor effects.

In Vivo Preparation of CAR-M

However, in vitro preparation of CAR-M also shares similar challenges with CAR-T therapies, and needs to overcome issues such as longer production cycles and high costs in large-scale preparation. As a result, more and more R&D teams are gradually turning to consider lower-cost in vivo CAR-M therapies, and are beginning to focus on the therapeutic prospects and potential of in vivo macrophage reprogramming therapies.

• Carisma utilizes LNP as a vehicle to deliver mRNA encoding CAR to endogenous myeloid cells in vivoso that it can be translated into CAR proteins, transforming macrophages into CAR-Ms capable of recognizing and attacking specific tumor cells for targeted anti-tumor activity.
• Myeloid Therapeutics is also developing in vivo CAR-M to treat advanced or metastatic epithelial tumors through LNP-mRNA in vivo preparation of CAR-M cell therapies targeting TROP2.

The combination of CAR technology and the dynamic capabilities of macrophages forms a powerful alliance in the fight against cancer and offers hope to cancer patients. As the journey continues, Creative Biolabs facilitates the unfolding of in vivo CAR-macrophage therapies.

Reference

1. Moreno, Carlos, et al. "Alternative CAR therapies: recent approaches in engineering chimeric antigen receptor immune cells to combat cancer." Biomedicines 10.7 (2022): 1493.