Engineered immune cells have been the topic of investigation for the last few decades. Just 11 years ago a child was treated with chimeric antigen receptor (CAR)-T cell therapy and has been in remission with no relapse in acute lymphoblastic leukemia (ALL). CAR-T cell therapy is a form of adoptive T cell therapy in which T cells, the immune cells responsible for targeting foreign invaders, are taken out of a patient, and engineered to retain specific proteins to recognize and target infected cells. The engineered T cells are then reinfused into the patient to attack the disease. This therapy is currently associated with cancer and is under investigation to treat solid tumors in addition to hematologic malignancies. T cells are just one type of immune cell that can kill or lyse cancer cells. Another cell that can directly target cancer cells includes Macrophages. In addition to degrading infected cells, macrophages take up foreign peptides and present these antigens on their surface to activate T cells. These cells also help maintain homeostasis in response to infection through regulatory and repair functions. Due to their multiple functions and ability to target tumor cells, macrophages are another possible cell to engineer for adoptive transfer therapy.
CAR-macrophage therapy is an exciting therapeutic option with the same goal as CAR-T cell therapy. Macrophages from the patient are engineered to target specific antigens or peptides from infected cells and reinfused back into the patient. While CAR-T cell therapy has shown tremendous promise, there are issues with these cells trafficking to the tumor. CAR-macrophages have the advantage of homing and infiltrating the tumor in addition to also activating T cells present in the tumor microenvironment (TME). CAR therapies are categorized by generation based on how they have evolved. With each generation more immunostimulatory molecules are added to elicit a stronger immune response. The first-generation CAR-macrophage therapy had an immunostimulatory CD3ζ component and could phagocytose tumor cells through antigen recognition; however, efficacy was limited, and tumors continued to grow.
Scientists led by Dr. Jin Zhang, investigator at Zhejiang University, recently published in Nature Immunology demonstrating a second-generation Car-macrophage therapy which enhances therapeutic efficacy in solid tumors. What is different about this CAR-macrophage therapy is that in addition to the immunostimulatory CD3ζ component, it also has a toll-like receptor 4 intracellular toll/IL1R (TIR) component, which further activates the immune response. This is novel because toll-like receptors (TLRs) signal ‘danger’ to the immune system and allow immune recognition of the tumor. Therefore, this therapy will generate a stronger immune response against the cancer. Additionally, Zhang and others “engineered induced pluripotent stem cell-derived macrophages” (iMACs), which allow the cells to not only have more lysis capacity against the tumor, but also polarizes the cells toward an anti-tumor phenotype or characteristic (M1). This M1 phenotype allows the CAR-iMACs to regulate the TME and more aggressively target the cancer cells. Overall, this second-generation CAR-macrophage therapy provides improved and prolonged anti-tumor response.
Zhang and others developed a novel CAR-macrophage therapy which significantly improves cancer treatment and demonstrated its efficacy in established models. This provides additional therapeutic options for patients once it is further tested and brought to clinical trials. This second-generation CAR-iMAC therapy has the potential to not only improve anti-tumor treatment in solid tumors, but also enhance patient survival in hard-to-treat tumors.
Published, Jin Zhang, Zhejiang University, Nature Immunology
