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In Vivo Activation of Signal Transducer and Activator of Transcription 1 after CD154 Gene Therapy for Chronic Lymphocytic Leukemia Is Associated with Clinical and Immunologic Response¹

Department of Medical Oncology, Dana-Farber Cancer Institute and Departments of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115 [T. E. B., D. A. F.]; Department of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [D. Z., D. N.]; Leukemia Department, M. D. Anderson Cancer Center, Houston, Texas [W. G. W.]; Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California [L. Z. R., T. J. K.]; and The Chronic Lymphocytic Leukemia Research Consortium [T. E. B., W. G. W., L. Z. R., D. Z., D. N., T. J. K., D. A. F.]

Purpose: Signal transducer and activator of transcription (STAT) proteins are important regulators of physiological stimuli in lymphocytes. Biological therapies directed at lymphocytic malignancies such as chronic lymphocytic leukemia (CLL) may be mediated by these transcription factors. One such approach, CD154 (CD40-ligand) gene therapy, involves expressing CD154 on malignant B cells from CLL patients by transduction with an adenovirus vector after which the cells are reinfused into the patients. To determine the intracellular signaling pathways that underlie the clinical and immunological responses observed in patients from a Phase I study of CD154 gene therapy, CLL cells from these patients were examined for changes in STAT signaling events.

Experimental Design: CLL cells from patients who underwent CD154 gene therapy were analyzed for changes in STAT signaling by Western blot analysis and electrophoretic mobility shift assay. Activation of STAT1 was correlated with patient response to therapy.

Results: Tyrosine phosphorylation of STAT1 was detected in the nontransduced CLL cells in 9 of 11 patients 24 h after infusion, but not before. Activation of STAT1 was associated with clinical response, as measured by decreased absolute lymphocyte count, and immunological response, as measured by elevated plasma levels of IFN-.

Conclusion: This study indicates that STAT signaling may be an important mediator of biological treatments, such as CD154 gene therapy, and that early STAT1 activation may predict response to this novel treatment.

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