CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia

May 15, 2011

BlankCD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia

1.. G. Wierda,

2.. Mark J. Cantwell,

3.. J. Woods,

4.. Z. Rassenti,

5.. E. Prussak, and

6.. J. Kipps

+ Author Affiliations

1.. 1 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.

Abstract

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.

For full text see

Recommended Posts