CAR-Macrophages: The Next Step in Solid Tumor Immunotherapy?

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Shan Grewal

Cancer has long been a formidable adversary in the world of medicine, but recent advancements in the field of immunotherapy have offered new hope in the battle against this complex disease. Immunotherapy is a revolutionary approach that harnesses the body’s immune system to target and eliminate cancer cells. 

One of the most exciting developments in this field is Chimeric Antigen Receptor T-cell (CAR-T) therapy. An antigen is any molecular pattern that immune cells can recognize. In cancer, antigens are often in the form of proteins uniquely expressed at the cell surface by neoplastic cells. T Cells are a type of lymphocyte (white blood cell) activated by other immune system components. When activated, some T Cells can kill host cells that are infected by an intracellular pathogen that would otherwise be able to evade the immune system.  As such, T cells can produce a highly potent and specific immune response against select antigens, although cancer cells are often able to inhibit this activity.1 In autologous CAR-T therapy, a patient’s T cells are isolated from their blood and genetically engineered in the lab to express a CAR receptor.2 The CAR on the T-cell surface will recognize a specific antigen associated with cancer and activate the T cell to kill the antigen-expressing cancer cell just like it would with an infected cell.2 This process, in essence, turns the patient’s immune system into a formidable weapon against cancer.

CAR-T therapy has achieved impressive results in specific hematological cancers, such as acute lymphoblastic leukemia and diffuse large B-cell lymphoma; however, its success in treating solid tumors (tumors in solid organs, unlike bloodborne tumors) has been limited.2 Solid tumors present unique challenges, as their microenvironment is often characterized by a dense extracellular matrix, limited blood supply, and factors that suppress the immune response.2 These obstacles make it difficult for CAR-T cells to infiltrate solid tumors and effectively kill cancer cells.

In the quest to address the limitations of CAR-T therapy in solid tumors, a promising new avenue of research has emerged: Chimeric Antigen Receptor-Macrophages (CAR-Ms). Macrophages are a different type of immune cell that plays a crucial role in our innate immune response, the body’s first line of defense. In some solid tumors, macrophages can account for 50% of the tumor bulk. CAR-Ms are engineered macrophages modified to express similar chimeric antigen receptors.3 Compared to T-cells, macrophages have an exceptional ability to infiltrate tissues and engulf and digest cancer cells in a process called “phagocytosis”. Also, they are excellent at signaling and recruiting other immune cells to the disease site.3,4 As such, CAR-Ms combines the remarkable antigen-targeting capabilities of CAR technology with the innate tumor-penetrating and phagocytic proficiency of macrophages.

While CAR-Ms represent a relatively new area of research, several studies have already demonstrated their potential in preclinical and early-phase clinical trials. Most notably, a Phase 1 clinical trial in Pennsylvania using a CAR-M directed against HER2, a protein expressed on the surface of a variety of solid tumors, and reported to be safe thus far. On a molecular level, the anti-HER2 CAR-M increased the number of reactive immune cells around the cancers, a positive indicator that the CAR-M is working and recruiting other immune cells (e.g., white blood cells).5 United States Food and Drug Administration (FDA) even granted fast-track designation to the CAR-M product tested in this trial.3

The development of CAR-Ms holds great promise, but several challenges lie ahead. A critical challenge is the optimization of CAR-Ms engineering and production processes, ensuring safety, efficacy, and scalability. Another difficulty for CAR-Ms, shared with CAR-Ts, is antigen discovery. In some malignancies, these antigens are fortunately well-defined and effective (e.g., CD19 in acute lymphoblastic leukemia, MUC1 in breast cancer).6 However, finding a perfect target in certain solid tumors has proven to be a more complicated task.6 For instance, gliomas (tumors of glial cells in the brain) have the highest number of CAR-T trials of any solid tumor, yet none have reached the broader population.7 Solid tumors often exhibit a heterogeneous mix of cells with varying antigen expression, making it challenging to identify a single, universally applicable target within and between patients. This heterogeneity can also lead to antigen loss, where cancer cells evolve to no longer express the targeted antigen, rendering CAR-M/T therapy ineffective.6

Nevertheless, as scientists continue to unlock CAR-Macrophages’ potential, the future of immunotherapy for solid tumors should give hope to physicians and patients alike. Perhaps within our lifetime, cancer research may be able to shift away from chemotherapy and its associated toxicities and leverage the specificity and potency of our immune system to clear solid tumors. Some have already considered combining CAR-Ts, CAR-Ms, and CAR-engineered versions of other immune cells, such as Natural Killer (NK) Cells targeting cancer.3 With ongoing research and a focus on patient safety, CAR-directed therapy could revolutionize cancer treatment, providing new hope for individuals battling solid tumors. This innovative approach showcases the incredible progress being made in the fight against cancer and underscores the potential for even more effective and targeted treatments on the horizon in the era of immunotherapy.

Edited by Hema Saranya Ilamathi

References

  1. Waldman, A. D., Fritz, J. M., & Lenardo, M. J. (2020). A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nature Reviews. Immunology, 20(11), 651–668. https://doi.org/10.1038/s41577-020-0306-5
  2. Sterner, R. C., & Sterner, R. M. (2021). CAR-T cell therapy: current limitations and potential strategies. Blood Cancer Journal, 11(4), 69–11. https://doi.org/10.1038/s41408-021-00459-7
  3. Wang, S., Yang, Y., Ma, P., Zha, Y., Zhang, J., Lei, A., & Li, N. (2022). CAR-macrophage: An extensive immune enhancer to fight cancer. EBioMedicine, 76, 103873. https://doi.org/10.1016/j.ebiom.2022.103873
  4. Pan, K., Farrukh, H., Chittepu, V. C. S. R., Xu, H., Pan, C.-X., & Zhu, Z. (2022). CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy. Journal of Experimental & Clinical Cancer Research, 41(1), 119–119. https://doi.org/10.1186/s13046-022-02327-z
  5. Reiss, K. A., Yuan, Y., Ueno, N. T., Johnson, M. L., Gill, S., Dees, E. C., Chao, J., Angelos, M., Shestova, O., Serody, J. S., Priceman, S., Barton, D., Swaby, R. F., Ronczka, A., Condamine, T., Cushing, D., Qureshi, R., Kemp, M., Klichinsky, M., & Abdou, Y. (2022). A phase 1, first-in-human (FIH) study of the anti-HER2 CAR macrophage CT-0508 in subjects with HER2 overexpressing solid tumors. Journal of Clinical Oncology, 40(16_suppl), 2533–2533. https://doi.org/10.1200/JCO.2022.40.16_suppl.2533
  6. Guzman, G., Reed, M. R., Bielamowicz, K., Koss, B., & Rodriguez, A. (2023). CAR-T Therapies in Solid Tumors: Opportunities and Challenges. Current oncology reports, 25(5), 479–489. https://doi.org/10.1007/s11912-023-01380-x
  7. Barros, L. R. C., Couto, S. C. F., da Silva Santurio, D., Paixão, E. A., Cardoso, F., da Silva, V. J., Klinger, P., Ribeiro, P. do A. C., Rós, F. A., Oliveira, T. G. M., Rego, E. M., Ramos, R. N., & Rocha, V. (2022). Systematic Review of Available CAR-T Cell Trials around the World. Cancers, 14(11), 2667-. https://doi.org/10.3390/cancers14112667

Image Credits: A scanning electron microscope of a macrophage. Source: National Institute of Allergy and Infectious Diseases

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