Generating a Novel CAR-Macrophage Therapy for Treatment of Solid Tumors

Recent studies have highlighted the important role of the immune system in determining tumor fate. In particular, Chimeric Antigen Receptor T-cell (CAR-T) has proven successful in treating hematological tumors. However, CAR-T therapy has demonstrated limited success in the treatment of solid tumors.

The limitation of CAR-T technology stems from the harsh conditions (ex. acidic and hypoxic) at tumor microenvironments (TME) which inhibit T-cell infiltration. In contrast, myeloid cells massively infiltrate tumors and are well-adapted to survive these conditions of TME, albeit they usually adopt a tumor-promoting phenotype rather than a cytotoxic one.

Recently, this project has discovered that at the onset of cancer development, tumor cells are found coated with IgM antibodies and co-incubation of myeloid cells with such IgM-coated tumor cells induces secretion of lytic granules and massive tumor cell death as a result.

These findings open a new venue for designing a novel immunotherapy of CAR-Macrophage by equipping monocytes with CAR that would specifically bind to tumor antigens. This antigen-antibody binding consequently induces IgM-driven signaling cascades within CAR-macrophages.

However, I discovered that myeloid cells prevent expression of CAR by recognizing its extracellular, antibody-derived component and that the mechanism behind inhibition of CAR expression resembles that of endoplasmic reticulum (ER) stress.

Overall, this work highlights the challenges in developing CAR-macrophage and provides a novel framework for utilizing the specific recognition capacity of the adaptive immune system and the ability of myeloid cells to better survive at tumor microenvironment.