Immunomodulatory preconditioning with cyclophosphamide enhances the inhibitory effect of adenovirus gene transfer of IL-12 on growth and metastasis of colorectal carcinoma in mice.

MALVICINI M; PICCIONI F; BAYO J; FIORE E; ATORRASAGASTI C; GARCÍA MG; ALANIZ L; AQUINO JB; SCHAROVSKY G; MATAR P; MAZZOLINI G

Rio de Janeiro

Congreso; Simposio Sudamericano de Terapia Génica; 2011

Colorectal carcinoma (CRC) is the second most common cancer worldwide and surgery is the primary treatment but only it can be performed in 20% of patients. New therapeutic options are needed. Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor effects in several models but toxicity has been associated with its systemic application. Gene transfer has emerged as a tool to express therapeutic genes into the tumor milieu avoiding systemic toxicity. The aim of this study was to analyze whether sub-therapeutic doses of an adenovirus encoding IL-12 (AdIL-12) might synergize with single low or metronomic low doses of cyclophosphamide (Cy) for the treatment of CRC Balb/c mice were injected with CT26 cells intrahepatic or subcutaneously (day 0); distributed in groups (day 7) and treated with: saline; Cy 50 mg/Kg i.p (single dose, day 7); AdIL-12 109 TCID50 i.t (day 8); Cy single dose + AdIL-12; Cy 25 mg/kg i.p (metronomic dose, 3 times a week) or Cy metronomic dose + AdIL-12. Tumor volume was measured and samples of peripheral blood and spleen were taken for immunological studies. Low dose of Cy with AdIL-12 resulted in a potent antitumoral effect higher than each agent alone in all of schedules tested. The percentages of complete tumor regressions induced by combined treatment were 50% and 40% both in s.c and liver metastasis models respectively. Metronomic dose of Cy +AdIL-12 was not superior to single dose of Cy+AdIL-12. However, both schedules decreased the number of regulatory T cells (Tregs) in peripheral blood and spleen of treated mice in comparison with untreated or single agent-treated mice (p