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Intrapulmonary Administration of CCL21 Gene-Modified Dendritic Cells Reduces Tumor Burden in Spontaneous Murine Bronchoalveolar Cell Carcinoma

¹ Department of Medicine, Lung Cancer Research Program and ² Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles; ³ Molecular Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; and ⁴ Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland

Requests for reprints: Sherven Sharma, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, 37-131 Center for Health Sciences, 10833 LeConte Avenue, Los Angeles, CA 90095-1960. Phone: 310-478-3711, ext. 41863; Fax: 310-268-4809; E-mail: sharmasp{at}ucla.edu.

The antitumor efficiency of dendritic cells transduced with an adenovirus vector expressing secondary lymphoid chemokine (CCL21) was evaluated in a murine model of spontaneous bronchoalveolar cell carcinoma. The transgenic mice (CC-10 TAg) express the SV40 large T antigen (TAg) under the Clara cell promoter, develop bilateral, multifocal, and pulmonary adenocarcinomas, and die at 4 months as a result of progressive pulmonary tumor burden. A single intratracheal administration of CCL21 gene-modified dendritic cells (DC-AdCCL21) led to a marked reduction in tumor burden with extensive mononuclear cell infiltration of the tumors. The reduction in tumor burden was accompanied by the enhanced elaboration of type 1 cytokines [IFN-, interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor] and antiangiogenic chemokines (CXCL9 and CXCL10) but a concomitant decrease in the immunosuppressive molecules (IL-10, transforming growth factor-ß, prostaglandin E₂) in the tumor microenvironment. The DC-AdCCL21 therapy group revealed a significantly greater frequency of tumor-specific T cells releasing IFN- compared with the controls. Continuous therapy with weekly intranasal delivery of DC-AdCCL21 significantly prolonged median survival by >7 weeks in CC-10 TAg mice. Both innate natural killer and specific T-cell antitumor responses significantly increased following DC-AdCCL21 therapy. Significant reduction in tumor burden in a model in which tumors develop in an organ-specific manner provides a strong rationale for further evaluation of intrapulmonary-administered DC-AdCCL21 in regulation of tumor immunity and genetic immunotherapy for lung cancer.(Cancer Res 2006; 66(6): 3205-13)

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