Nevertheless, in CLL patients, CD4+ T cells stimulate CLL cell survival and proliferation by secreting multiple chemokines/cytokines and through direct contact with the CD40 ligand (27, 36, 94), and CD8+ T cells are persistently activated and expanded within the CLL microenvironment and gradually become pseudo-exhausted (5, 50, 52), finally resulting in T-cell immune tolerance and the loss of their anti-tumor activity (27), which has been reported to be causative of the poor response to CAR-T cell therapies for CLL patients (95–97). This evidence concerns the gene CD4 and B-cell chronic lymphocytic leukemia.