CD154 gene therapy for human B-cell malignancies.
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.
Messmer
Davorka
D
Moores Cancer Center, University of California San Diego, 3855 Health Science Dr., Number 0820, La Jolla CA 92093-0820, USA.
Kipps
Thomas J
TJ
D023201:CD40 Ligand / Q000235:genetics* / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods / Q000639:trends; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy*
D023201:CD40 Ligand