CAR-M Therapy: Hope for Treating Complex Tumours

Researchers from South Korea have presented an innovative approach to cancer immunotherapy that could significantly expand the capabilities of existing treatment methods, such as CAR-T (chimeric antigen receptor T-cell therapy). The team from the Korean Research Institute of Chemical Technology (KRICT) led by Dr. Chi-Hoon Park has developed a new technology based on the use of macrophages with chimeric antigen receptors (CAR-M). This method promises to overcome the limitations of CAR-T therapy, especially in treating solid tumours such as lung or liver cancer, and open new prospects in the fight against oncological diseases.

What is CAR-M and How Does it Differ from CAR-T

Traditional CAR-T therapy involves extracting the patient's T-cells, genetically modifying them to recognize and destroy cancer cells, and then reintroducing them into the body. This method has shown outstanding results in treating blood cancers, such as acute lymphoblastic leukemia and lymphomas. However, when treating solid tumours, CAR-T faces significant obstacles, such as low T-cell infiltration into tumour tissue and a complex tumour microenvironment that suppresses the immune response.

Macrophages, unlike T-cells, have a unique ability to effectively penetrate solid tumours and interact with their microenvironment. This makes them a promising platform for immunotherapy. However, until now, the use of macrophages has been limited by the instability of genetic modifications and the toxicity of gene delivery methods. The KRICT team has overcome these barriers by developing a protocol for the stable insertion of synthetic genes encoding CAR into macrophages derived from human peripheral blood using a lentiviral delivery system.

Key Innovations Include:

• Elimination of toxicity: researchers have abandoned the use of polybrene, a cationic polymer traditionally used to enhance viral penetration but toxic to macrophages. Instead, they increased the virus exposure time from 1.5 to 16 hours, allowing for safe and effective gene delivery.
• Optimization of transduction time: it was found that the efficiency of gene uptake depends on the stage of macrophage differentiation. Infection on day 7 of differentiation significantly improved gene expression.
• Improved viral penetration: the team modified the VSV-G protein, a key component of the lentiviral system, optimizing its codon sequences. This increased the efficiency of gene delivery.
• Stable gene expression: the use of the EF1α promoter ensured stable expression of CAR in macrophages for up to 20 days, which was previously unattainable.

These improvements have led to the creation of CAR-M macrophages that demonstrate high stability and effectiveness in combating cancer cells.

Effectiveness of CAR-M in Laboratory Conditions

In experiments, CAR-M cells were tested on cancer cell cultures, including Nalm6 (acute lymphoblastic leukemia) and Raji (B-cell lymphoma) lines. Results recorded using fluorescent microscopy showed that CAR-M macrophages actively engulf and destroy cancer cells. This confirms their potential as a powerful tool for immunotherapy.

Importantly, CAR-M demonstrated the ability to effectively infiltrate solid tumours, making them a promising solution for treating lung, liver, pancreatic, and other complex oncological diseases. Unlike CAR-T, which are primarily limited to hematological malignancies, CAR-M could become a universal platform for combating a wide range of tumours.

Prospects for Clinical Application

The KRICT research group is already planning to scale up the production of CAR-M and develop protocols for their clinical application. The successful implementation of these plans could lead to the creation of a new generation of immunotherapeutic drugs that will complement or even surpass existing treatment methods.

Dr. Chi-Hoon Park emphasized the significance of the discovery: “This is the first study demonstrating stable CAR expression in macrophages derived from peripheral blood using lentiviral technology. Our work paves the way for the development of new cancer treatment strategies.” KRICT President Yong-Kook Lee added: “This technology has the potential not only to complement CAR-T therapy but also to significantly expand the arsenal of immuno-oncological methods, offering patients new hopes for recovery.”

The Future of Immunotherapy

The development of CAR-M is an important step in the evolution of cancer immunotherapy. Unlike previous approaches that were limited either by the type of cancer or the stability of genetic modifications, CAR-M offers a more flexible and universal solution. Their ability to penetrate solid tumours and maintain stable activity opens new horizons for treating oncological diseases that were previously considered difficult to cure.

Furthermore, the CAR-M technology can be adapted for the treatment of other immune-related diseases, such as autoimmune disorders or chronic infections. Researchers are also considering the possibility of combining CAR-M with other immunotherapy methods, such as checkpoint inhibitors, to enhance the therapeutic effect.

However, before the widespread clinical application of CAR-M, several challenges must be overcome. Further research is needed to assess the safety and efficacy of the method in animal models and clinical trials. Standardized production protocols will also need to be developed to ensure scalability and accessibility of the therapy for patients worldwide.