About
A CAR, is a tumor-specific engineered antigen receptor, combining the highly specific binding domain of an antibody to the intracellular signalling domain of a T cell receptor (CD3e, CD28, 4-1BB). Once expressed in T cells, these engineered cells are capable of finding, migrating and killing tumor cells in vivo. CAR T cells have yield tremendous clinical results for the treatment of liquid tumors (B cell malignancies) and are now recognized as a breakthrough personalized cell therapy. However, their success in treating solid tumors faces some bottlenecks, possibly due to their limited migration and survival in the highly immunosuppressed tumor microenvironment. Solid tumors represent the most frequent type of cancer, thus novel cell-based therapeutic strategies need to be envisioned to treat these type of cancer. Macrophages represent the most abundant population at the tumor site and can arise either from tissue-specific macrophages or from blood-derived monocytes. Macrophages, which belong to the innate arm of the immune system, are capable of engulfing and digesting intruders following the recognition of danger associated pattern or antibody coating. Moreover, they are capable of recruiting the adaptive arm of the immune system and such “vaccinal effect” would be highly valuable in the context of anti-tumor therapies. Therapeutic strategies that trigger phagocytosis rely mainly on monoclonal antibodies (e.g. anti-CD20 antibody, anti-HER2 antibody) which may not efficiently diffuse within the densed tumor microenvironment to reach macrophages and induce phagocytosis. Thus, there is a need to develop novel therapeutic strategies overcoming these limitations and capable of efficiently eliminating solid tumor cells. Recently, a team showed that expression of a CAR into macrophages (CARpha) endowed the cells with potent phagocytosis ability. The therapy was shown to be efficient in a preclinical model of solid tumor and has now entered Phase-I clinical trial. However, critical questions remain to be addressed: What is the main mechanism of action of the CARpha therapy in vivo (e.g. tumour depletion through phagocytosis or initiation of an adaptive immune response)? How is CARpha activity impacted by different tumour types or tumour locations? Do CARpha have some therapeutic limitations in vivo (e.g. off-target toxicity, tumour infiltration, host engraftment, exhaustion)? And finally, how can the CARpha therapy be optimized for the treatment of solid tumours?