New advances in leukaemia immunotherapy by the use of Chimeric Artificial Antigen Receptors (CARs): state of the art and perspectives for the near future

Chimeric T-cell Antigen Receptors (CARs) are a fascinating bio-technologic step in the field of immunotherapy to orient the activity of immune cells towards specific molecular targets expressed on the cell surface of various tumours, including haematological malignancies. CARs are artificial T-cell receptors constituted by an antigen-recognizing extracellular domain derived from an antibody molecule linked to a T-cell triggering domain [1-4]. CARs are generated by joining the heavy and light chain variable regions of a monoclonal antibody, expressed as a single-chain Fragment variable (scFv) molecule, to an intracellular signalling domain, usually the zeta-chain of the TCR/CD3 complex or the gamma-chain from the Fc-epsilon-RI receptor Figure 1. T lymphocytes genetically engineered to express CARs exhibit specific lysis towards tumour cells and cytokine secretion upon exposure to the respective target antigen. The CAR-mediated effector function may produce sustained tumour cell lysis more likely than humoral immune responses alone, based on the use of monoclonal antibodies. The perforin/granzyme killing mechanism may be effective against cells that are relatively resistant to antibody and complement, while cytokine secretion recruits additional components of the immune system, amplifying and prolonging the anti-tumour immune response. Moreover, effector T cells display efficient tumour penetration and homing capabilities [1-4].The CAR approach permits to overcome the major limitations associated with the use of a "classical" TCR transgenic molecule. In fact, target recognition by CAR is non-MHC restricted and independent of antigen processing, therefore allowing its use in patients with different haplotypes and bypassing tumour escape due to MHC-molecules down-regulation. In addition, CARs can be targeted toward molecules other than peptides, like carbohydrates and glycolipids, and there is no risk to trigger unpredictable and potentially harmful specificities, as it