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Department of Surgery [F. S., C. P. H., K. O., D. M. M.] and Comprehensive Cancer Center [A. L. R., P. M. S., N. S. Y.], University of Wisconsin-Madison, Madison, Wisconsin 53792

Effective eradication of established tumors and generation of a lasting systemic immune response is an important goal for cancer gene immunotherapy. The method of gene delivery may also be critical for the generation of an effective antitumor response. We compared the level of transgene expression and antitumor activity of two different interleukin (IL)-12 DNA preparations (naked DNA versus DNA lipid complex). Established murine adenocarcinoma (CT26) and renal cell carcinoma (Renca) tumors in BALB/c mice were treated by direct intratumoral injection of a nonviral plasmid DNA vector encoding the murine IL-12 (mIL-12) gene, either alone (naked) or in complexes with cationic lipid. Both treatments resulted in the same percentage (87%) of mice undergoing a complete tumor regression of the CT26 tumor. For the Renca tumor model, complete tumor regression was observed in 67 and 75% of animals treated with naked mIL-12 DNA and mIL-12 DNA plus lipid, respectively. Mice that were rendered tumor free for >50 days by mIL-12 gene therapy rejected a subsequent challenge of parental tumor cells but not of an unrelated, syngeneic tumor. The marked reduction of tumor growth in tumor-bearing mice treated with mIL-12 cDNA was associated with the augmentation of tumor-specific cytotoxic T cells, enhanced production of IFN- in spleen and lymph node cells, and increased splenomegaly and lymphadenopathy. The CD8⁺:CD4⁺ ratio in tumor-infiltrating lymphocytes was significantly increased in the tumor-bearing mice treated with mIL-12 DNA alone and mIL-12 cDNA plus lipid as compared with a control vector-treated group. These results indicate that direct intratumoral gene transfer with naked nonviral IL-12 DNA provides an effective and simple method for the treatment of murine tumors, suggesting an approach for clinical application.

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