Intratumoral coinjection of adenoviral vectors expressing IL-2 and IL-12 results in enhanced frequency of regression of injected and untreated distal tumors

Gene Ther. 1998 Oct;5(10):1400-9. doi: 10.1038/sj.gt.3300731.

Abstract

We have studied the ability of adenoviral (Ad) vectors expressing the cytokines IL-2 or IL-12 to mediate regression of established tumors in a mouse model of mammary adenocarcinoma. Previous results indicated that intratumoral injection of vectors expressing IL-2 (AdCAIL-2), or IL-12 (AdmIL-12.1) induced complete tumor regression in approximately 30-40% of treated animals. In the current studies, we investigated the mechanism of tumor killing in responding animals and the efficacy of AdIL-2 and AdIL-12 vector administration in combination compared with the use of either vector alone. Animals bearing subcutaneous mammary tumors were injected intratumorally with Ad vectors expressing IL-2 or IL-12 or were coinjected with both vectors. Animals receiving the combination treatment responded substantially better than animals which had received either vector alone, with 65% of animals treated with both vectors undergoing complete tumor regression. In all three treatment regimens, tumor regression was associated with the presence of specific antitumor antigen cytotoxic T-lymphocytes (CTLs), which secreted elevated levels of IFN-gamma. Consistent with circulating CTLs being involved in regression, when animals bearing bilateral tumors were inoculated in a single tumor with IL-2 or IL-12 expressing vectors, both tumors regressed in many cases. Again, treatment with both AdCAIL-2 and AdmIL-12.1 was most effective, with 63% of animals undergoing complete regression of both treated and untreated tumors, compared to 18 or 22% of animals injected with either AdCAIL-2 or AdmIL-12.1 alone. These data indicate that the combination of IL-2 and IL-12 is a more effective inducer of antitumor immune responses than either one alone, and that the resulting antitumor responses are effective in mediating the regression of distal untreated tumors, a property which may aid in the treatment of metastatic disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / therapy*
  • Adenoviridae
  • Animals
  • Female
  • Gene Expression
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Immunotherapy / methods*
  • Injections, Intralesional
  • Interleukin-12 / genetics
  • Interleukin-2 / genetics
  • Interleukins / genetics*
  • Mammary Neoplasms, Experimental / immunology
  • Mammary Neoplasms, Experimental / therapy*
  • Mice
  • Mice, Transgenic
  • T-Lymphocytes, Cytotoxic / immunology

Substances

  • Interleukin-2
  • Interleukins
  • Interleukin-12