CD154 gene therapy for human B-cell malignancies

Ann N Y Acad Sci. 2005 Dec;1062:51-60. doi: 10.1196/annals.1358.008.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • CD40 Ligand / genetics*
  • CD40 Ligand / therapeutic use*
  • Genetic Therapy* / methods
  • Genetic Therapy* / trends
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Leukemia, Lymphocytic, Chronic, B-Cell / therapy*

Substances

  • CD40 Ligand