Blood, 1 November 2000, Vol. 96, No. 9, pp. 2917-2924
PLENARY PAPER
CD40-ligand (CD154) gene therapy for chronic lymphocytic
leukemia
William G. Wierda,
Mark J. Cantwell,
Sandra J. Woods,
Laura Z. Rassenti,
Charles E. Prussak, and
Thomas J. Kipps
From the Division of Hematology/Oncology, Department of
Medicine, and the UCSD Human Gene Therapy Program, University of
California-San Diego, La Jolla, CA; Immunogenex, Inc, La Jolla, CA; and
Molecular Medicine/LLC, UCSD, La Jolla, CA.
Chronic lymphocytic leukemia (CLL) cells can be made to express
recombinant CD40-ligand (CD154) by transduction with a
replication-defective adenovirus vector (Ad-CD154).
Ad-CD154-transduced and bystander leukemia cells become highly
effective antigen-presenting cells that can induce CLL-specific
autologous cytotoxic T lymphocytes in vitro. This study investigated
the immunologic and clinical responses to infusion of autologous
Ad-CD154-CLL cells in patients with CLL. After a one-time bolus
infusion of autologous Ad-CD154-transduced leukemia cells, there was
increased or de novo expression of immune accessory molecules on
bystander, noninfected CLL cells in vivo. Treated patients also
developed high plasma levels of interleukin-12 and interferon-
, the
magnitudes of which corresponded to absolute blood CD4+
T-cell counts before therapy. On average, patients experienced a
greater than 240% increase in absolute blood T-cell counts within 1 to
4 weeks of treatment. Moreover, treatment increased the numbers of
leukemia-specific T cells, demonstrated by autologous ELISPOT assay and
mixed lymphocyte reactions. These biologic effects were associated with reductions in leukemia cell counts and lymph node size.
Treatment did not induce autoimmune thrombocytopenia or hemolytic
anemia and no dose-limiting toxicity was observed. This approach may
provide a novel and effective form of gene therapy for patients with
this disease.
