CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia.
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-gamma, 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.
Wierda
W G
WG
Division of Hematology/Oncology, Department of Medicine, and the UCSD Human Gene Therapy Program, University of California-San Diego, La Jolla, CA.
Cantwell
M J
MJ
Woods
S J
SJ
Rassenti
L Z
LZ
Prussak
C E
CE
Kipps
T J
TJ
D000256:Adenoviridae; D000328:Adult; D000368:Aged; D018791:CD4 Lymphocyte Count; D023201:CD40 Ligand / Q000235:genetics* / Q000502:physiology; D016207:Cytokines / Q000097:blood; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000628:therapy*; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D016207:Cytokines; D011994:Recombinant Proteins; D023201:CD40 Ligand