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Amount of Interleukin 12 Available at the Tumor Site Is Critical for Tumor Regression¹

Division of Experimental Oncology D, Instituto Nazionale Tumori, Via Venezian I, 20133 Milan [M. P. C., M. V., F. S., M. P., C. C., C. M.], and Department of Experimental Medicine and Pathology, 2nd Chair of Pathology, University of Rome "La Sapienza," 00100 Rome [A. S.], Italy

The C26 colon carcinoma is resistant to systemic recombinant interleukin 12 (rIL-12) therapy. Transduction of C26 with genes encoding the two subunits of murine IL-12 to release 30–80 pg/ml resulted in delayed tumor onset after injection of 5 x 10⁴ cells into syngeneic BALB/c mice and in 40% tumor regression after injection into CD4-depleted mice. Here, we analyzed the activity of rIL-12 (1 µg/day) against C26 grown into CD4-depleted mice. Like in mice given injections of interleukin 12 (IL-12) gene-transduced C26 cells, depletion of CD4⁺ cells led to tumor regression in 6 of 14 mice, and immunocytochemical characterization of tumor-infiltrating leukocytes showed abundant infiltration by CD8⁺ T cells and asialoGM1⁺ natural killer cells, which were scanty in tumors from nondepleted mice. On the basis of the percentage of tumor regression and leukocyte infiltration we can conclude that, in the C26 system, systemic rIL-12 (1 µg/day) produces the same results as 30–80 pg/ml IL-12 released at the tumor site.

A new polycistronic retroviral vector was then used to increase the amount of IL-12 produced by C26-transduced cells. C26 cells releasing 5 ng/ml IL-12, nearly 100 times more than the above-mentioned transduced cells, were tumorigenic in less than 50% of the mice given injections of 5 x 10⁴ cells. In mice given injections of 5 x 10⁵ cells, an initial tumor take of 100% followed by a complete tumor regression. Tumor regression was associated with infiltration of CD8⁺ and asialoGM1⁺ cells, and mice that remained tumor free were immune to a rechallenge of nontransduced C26 cells. The results indicate that the amount of IL-12 made available at the tumor site may determine both the type and number of infiltrating leukocytes and the events leading to tumor regression as well as it may overcame host immunosuppression.

¹ This work was supported by the Italian Association for Cancer Research Special Program on Gene Therapy and by grants from Consiglio Nazionale delle Ricerche Target Project Genetic Engineering and Applicazioni Cliniche della Ricerca Oncologica.

² To whom requests for reprints should be addressed. Phone: (39)2-2390252; Fax: (39)2-2362692.

Received 4/ 8/96. Accepted 4/17/96.

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