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Activation of Tumor-Specific CD8⁺ T Cells after Intratumoral Ad5-TRAIL/CpG Oligodeoxynucleotide Combination Therapy

Department of Urology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa

Requests for reprints: Thomas S. Griffith, Department of Urology, University of Iowa, 3204 MERF, 375 Newton Road, Iowa City, IA 52242-1089. Phone: 319-335-7581; Fax: 319-353-4556; E-mail: thomas-griffith{at}uiowa.edu.

CD8⁺ T-cell activation via cross-presentation of antigens from apoptotic tumor cells is controversial. Dendritic cells capture naturally shed tumor antigens and cross-present them to CD8⁺ T cells; unfortunately, the frequency of activated CD8⁺ T cells is often too low to mount an effective response against the tumor. By increasing the amount of antigen for presentation, a larger T-cell response can be theoretically elicited. We used a recombinant adenovirus encoding full-length murine tumor necrosis factor–related apoptosis-inducing ligand (Ad5-mTRAIL) to induce tumor cell apoptosis, and when given intratumorally to mice bearing experimental renal cell carcinoma (Renca) tumors, Ad5-mTRAIL minimally prolonged survival and induced a low level of CTL activity. To enhance dendritic cell efficiency, an immunostimulatory CpG oligodeoxynucleotide (CpG ODN) was combined with Ad5-mTRAIL. This combination therapy significantly augmented in vivo antigen-specific T-cell proliferation and CTL activity, as well as prolonged survival of Renca tumor-bearing mice. Interestingly, depletion of CD4⁺ or CD25⁺ cells before therapy further enhanced survival and in vivo CTL activity. In addition, tumor-free mice depleted of CD4⁺ cells were also able to reject a subsequent challenge of Renca cells, but not MHC-matched RM-11 prostate tumor cells, demonstrating the existence of immunologic memory. These results collectively show that local treatment with Ad5-mTRAIL and CpG ODN can augment tumor antigen cross-presentation resulting in T-cell proliferation, enhanced CTL activity, and increased animal survival. [Cancer Res 2007;67(24):11980–90]

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