Patients with chronic lymphocytic leukemia cells (CLL) who received a one-time bolus infusion of autologous leukemia cells transduced with adenovirus encoding recombinant CD154 experienced acute and long-term reductions in leukemia cell counts and lymph-node size. This was associated with increases in the numbers of leukemia-specific CD4+ T cells and high serum-levels of IL-12 and IFN-gamma. CD40-ligation induces CLL cells to express the proapoptotic molecule Bid and death receptors CD95 (Fas) and DR5, rendering CLL B cells first resistant and then sensitive to Fas-mediated apoptosis. Increasing sensitivity to Fas-mediated apoptosis was also due to differential expression of pro- and antiapoptotic proteins at early versus late time points after activation. Additional treatment with inhibitors to the X-linked inhibitor to apoptosis (XIAP) rendered the CD40-activated cells sensitive to Fas-mediated apoptosis even at early time points after CD40-activation, suggesting that XIAP inhibitors might enhance the effectiveness of CD154-based immune-gene therapy strategies for patients of B-cell malignancies.