A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice
Fecha
2009-11
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Editor
American Association for Cancer Research
Resumen
PURPOSE:
Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor effects in several animal models. However, serious toxicity has been associated with its systemic application in humans. Gene transfer has emerged as a tool to specifically express therapeutic genes into the tumor/peritumoral milieu, thus avoiding systemic toxicity. The aim of this study was to analyze whether subtherapeutic doses of an adenovirus encoding IL-12 (AdIL-12) might synergize with low immunopotentiating doses of cyclophosphamide in the treatment of colorectal carcinoma.
EXPERIMENTAL DESIGN:
The antitumor effect of combining a single low dose of cyclophosphamide with an intratumoral injection of AdIL-12 was evaluated in an in vivo murine colorectal carcinoma model. The immune responses achieved with different treatments were monitored, comparing the effect of combining both therapies with individual treatments.
RESULTS:
The combined therapy induced a complete tumor regression in >50% of mice in a synergistic fashion, and it significantly prolonged their survival. This strategy was superior to each single treatment in reducing both peripheral and splenic CD4+CD25+Foxp3+ regulatory T cells, increasing the number of activated dendritic cells, and inducing IFN-gamma-secreting CD4-positive T lymphocytes. Importantly, the combined treatment generated a powerful tumor-specific CTL response. Consistently, a significant reduction in IL-10 levels was found. Our data suggest that the combination of nontoxic doses of cyclophosphamide with AdIL-12 allows the generation of good antitumoral responses, thus avoiding undesired side effects of both agents.
CONCLUSIONS:
Our data strongly support the use of a combination of cyclophosphamide and AdIL-12 as a novel therapeutic strategy against colorectal carcinoma.
Descripción
Palabras clave
Combined immunotherapy, Cyclophosphamide gene therapy, Interleukin-12, Colorectal carcinoma
Citación
Malvicini, M., Rizzo, M., Alaniz, L., Pinero, F., Garcia, M., Atorrasagasti, C., Aquino, J. B., ... Mazzolini, G. (November 30, 2009). A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice. Clinical Cancer Research, 15, 23, 7256-7265