Regression of colon cancer and induction of antitumor immunity by intratumoral injection of adenovirus expressing interleukin-12

Abstract

Interleukin-12 (IL-12) has been shown to possess potent immunoregulatory and antitumoral effects. We have evaluated the anti-oncogenic potential and the mechanisms of the antitumoral effect of in vivo adenovirus-mediated transfer of IL-12 gene in a murine model of colon cancer. AdCMVIL-12 was constructed to permit coordinated production of p40 and p35 subunits of IL-12 gene to obtain the maximum IL-12 bioactivity. Infection of murine colon cancer CT-26 cells in vitro with AdCMVIL-12 resulted in the production of high levels of IL-12. In vivo gene therapy of colon cancer nodules by intratumoral injection of AdCMVIL-12 induced a local increase in IL-12 and interferon-␥ levels and a complete regression of the tumor in 26 of 34 (76%) mice. Tumor disappeared between days 7 and 10 after vector administration. The antitumoral effect was mediated by CD8 ϩ T cells and was associated with the generation of cytotoxic T lymphocytes against colon cancer cells. Animals that eliminated the tumor were protected against a second administration of neoplastic cells. Treatment with AdCMVIL-12 of one tumor nodule also caused regression of established tumors at distant sites. These data demonstrate that AdCMVIL-12 is a useful therapeutic tool for established colon cancer in mice and should be considered for application in humans.

IL-12 Gene Therapy Is an Effective Therapeutic Strategy for Hepatocellular Carcinoma in Immunosuppressed Mice

“…In prostate cancer, adenoviral-mediated IL-12 gene therapy had an antimetastatic effect in partial dependency on NK cells (42). In bladder carcinoma and colon cancer, adenoviral-mediated IL-12 gene therapy had a T cell-dependent local antitumor effect (43,44). Concerning the dependency of immune cells in the antiangiogenic effect induced by IL-12 (45), there are also contrasting reports (32,46).…”

Adenoviral Gene Transfer of Interleukin 12 into Tumors Synergizes with Adoptive T Cell Therapy Both at the Induction and Effector Level

“…Recombinant defective adenoviruses have been shown to be an excellent vehicle to deliver IL-12 to experimental tumors including a poorly immunogenic colon carcinoma (Caruso et al, 1996;Mazzolini et al, 1999). In our hands, high levels of IL-12 are produced on intratumoral injection of AdCMVIL-12 in CT26-derived tumors, leading to complete tumor regressions in 60-80% of cases.…”

“…Recombinant adenovirus carrying IL-12 (AdCMVIL-12) has been previously described (Mazzolini et al, 1999). Briefly, an expression cassette of IL-12 under the control of the cytomegalovirus (CMV) promoter was constructed encom passing IL-12 p35 cDNA, an internal ribosomal entry site (IRES), IL-12 p40 cDNA, and a polyadenylation signal.…”

“…In our hands, high levels of IL-12 are produced on intratumoral injection of AdCMVIL-12 in CT26-derived tumors, leading to complete tumor regressions in 60-80% of cases. In such cases, a potent antitumor CTL response was detected, depletion of CD8 1 cells abrogated the therapeutic effect, and a lymphocyte infiltrate accompanied tumor regressions (Mazzolini et al, 1999).…”

In vivo electroporation-mediated transfer of interleukin-12 and interleukin-18 genes induces significant antitumor effects against melanoma in mice

“…The standard 51 Crrelease assay was performed as described elsewhere. 54 Briefly, target cells were incubated with 370 kBq Na 2 51 CrO 4 for 60 min at 37°C. After washing, the target cells were seeded in a microtiter plate at a density of 1 × 10 4 /well.…”