Myeloid cell therapy

Adoptive cell therapy with T cells (Chimeric Antigen Receptor-T cell Therapy: CAR-T), which has shown excellent results in haematological cancers, consists of the genetic modification of patient immune cells to express on their surface a receptor (CAR) that specifically recognizes antigens overexpressed in tumor cells. There are currently available 7 FDA-approved and 6 EMA-approved CAR-T therapies, directed towards BCMA ("B cell maturation antigen" for multiple myeloma or towards CD19, for various lymphomas and B-cell leukemias. In addition to these industrially manufactured CAR-Ts, in Spain we have the particular case of ARI-0001 therapy for B-cell acute lymphoblastic leukaemia, being the first academic CAR-T approved in Europe. Numerous scientists are now investigating CAR-T therapies for the treatment of solid tumors, such as lung and breast cancer, glioblastoma, gastric, hepatic or colorectal cancer. However, their application in solid tumors faces the following significant limitations and challenges: i) poor capacity of T cells for extravasation, infiltration, and penetration into the tumor, ii) the heterogeneity and lack of specificity of tumor antigens, iii) T-cell exhaustion, characterized by the loss of their cytotoxic activity; mainly caused by the strong immunosuppressive nature of the tumor microenvironment (TME), mediated largely by the protumoral phenotype of tumor associated macrophages (TAMs); representing obstacles that prevent their use. For the treatment of solid tumors, and to overcome these issues, new investigations are considering alternative cell types. Among those, monocytes/macrophages are promising candidates to develop CAR-based therapies due to their intrinsic nature: efficient and rapid recruitment to the tumor, high tissue infiltration ability and tumor penetration, phagocytosis of tumor cells and antigen presentation, secretion of metalloproteinases and remodelling of the extracellular matrix, and high plasticity which allows the therapeutic manipulation of their polarization towards a M1-antitumor phenotype with capacity to kill cancer cells and trigger effective innate and adaptive immune responses.