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

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-γ, 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.

Multimodality Treatment Approaches in Pancreatic Cancer: Current Status and Future Perspectives

“…Finally, the neoplastic cells were inhibited in their growth kinetics. These results are interesting in view of the recently presented results from a phase I trial on CD40L gene transfer in CLL (5, 130).…”

Cytokine‐induced killer cells against autologous CLL: Direct cytotoxic effects and induction of immune accessory molecules by interferon‐γ

“…Kipps described a gene therapy approach where 3 × 10 8 –3 × 10 9 CD40L‐transfected autologous leukemia cells were infused into CLL patients. These cells induced the expression of immune accessory signals on noninfected bystander CLL cells, leading to T‐cell proliferation, cytokine secretion, expansion of leukemia specific T cells, reduction of CLL cell counts and lymph node size 33. It is conceivable that CIK cells, in addition to their immediate cytotoxicity, may have a similar effect in CLL patients, allowing activation of leukemia cells in vivo without the need for gene therapy.…”

CD154 Gene Therapy for Human B‐Cell Malignancies

“…In addition, treated patients had high plasma levels of the Th1‐type cytokines IL‐12 and IFN‐γ after infusion. T‐cell responses against autologous CLL cells, as evidenced by increased IFN‐γ secretion as well as T‐cell proliferation in an autologous MLR, were observed even at 6 months after treatment, indicating the development of memory antileukemia immune responses 22. Long‐term follow‐up studies showed that although the number of blood leukemic cells increased after a one‐time injection of Ad‐CD40L‐transduced cells, repeated injections resulted in a stabilized and reduced leukemia cell counts and disease stabilization.…”

“…1). 22 We investigated the immunological and clinical responses to infusion of Ad‐CD154‐CLL cells into eleven patients with progressive, intermediate, or high‐risk CLL. Patients received infusion of transduced CLL cells on average 44+/− 23 days after leukapheresis.…”