Chronic lymphocytic leukemia (CLL) is a malignancy arising from immune cells (B-lymphocytes) endowed with intrinsic antigen-presenting capabilities. Such a function however is lost during malignant transformation and CLL cells are well known for their inability to process and present antigens to the T-cell arm of the immune system. Instead, malignant CLL cells elicit a vast array of immune regulatory mechanisms conducive to T-cell dysfunction and immunosuppression. Previously, we have shown that treatment of CLL cells with the demethylating agent 5-aza-2'-deoxycytidine unleashed target antigen expression. Here we show for the first time that combining two epigenetic modifiers, 5-aza-2'-deoxycytidine and the histone deacetylase inhibitor LAQ824 effectively restores the immunogenicity of CLL cell lines as well as primary cells obtained from CLL patients. Indeed, such a combination induces the expression of novel and highly antigenic cancer-testis antigens (CTAs) and costimulatory molecules. These changes facilitate the formation of robust supramolecular activation complexes (SMAC) between CLL cells and responder T-cells leading to intracellular signaling, lytic granule mobilization, and polarization of functional and relevant T-cell responses. This cascade of T-cell activating events triggered by CLL cells with restored APC function, points to combined epigenetic modifier treatment as a potential immunotherapeutic strategy for CLL patients.