8647214

pubmed:Citation

6

Interleukin-12 (IL-12) promotes specific and long-lasting anti-tumor immunity mediated by T cells in a variety of murine tumor models. IL-12 also synergizes with B7.1 (CD80) co-stimulation to induce proliferation and cytokine production by both human and murine T cells in vitro. We evaluated the combined anti-tumor efficacy of IL-12 and B7.1 gene delivery in two apparently poorly immunogenic tumor models (TS/A and MCA207). In both of these models, expression of B7.1 and production of IL-12 in the inoculum led to improved anti-tumor immunity, with up to 80% long-term tumor-free animals (vs 0-20% of mice remaining tumor free when inoculated with either B7.1- or IL-12-transfected tumors alone). Tumor-free mice were capable of rejecting a subsequent rechallenge with the wild-type tumor in 66% of the cases. Cooperativity was dependent upon the level of IL-12 secreted by engineered cells. IL-12 delivery required B7 expression of therapeutic effects to be observed in these models. Vaccines provided at a site distal to a control, non-transfected tumor slowed (TS/A) or abrogated (MCA207) the progression of wild-type tumors. The synergistic anti-tumor effects associated with combined application of B7.1- and IL-12-transfected tumors were partially negated by systemic administration of the CD28-B7.1/B7.2 antagonist CTLA4-Ig or by inoculation with neutralizing antibodies directed against murine interferon-gamma or tumor necrosis factor-alpha, two cytokines elicited in response to IL-12 stimulation. These data support the potential clinical utility of combined gene therapy using IL-12- and B7.1-engineered autologous cells (tumor or fibroblasts) as a vaccine to elicit specific anti-tumor immunity.

eng

IM

MEDLINE

0014-2980

Print

NLM

1335-41

pubmed-meshheading:8647214-Animals, pubmed-meshheading:8647214-Antigens, CD, pubmed-meshheading:8647214-Antigens, CD28, pubmed-meshheading:8647214-Antigens, CD80, pubmed-meshheading:8647214-Antigens, Differentiation, pubmed-meshheading:8647214-CTLA-4 Antigen, pubmed-meshheading:8647214-Female, pubmed-meshheading:8647214-Immunoconjugates, pubmed-meshheading:8647214-Immunotherapy, pubmed-meshheading:8647214-Interferon-gamma, pubmed-meshheading:8647214-Interleukin-12, pubmed-meshheading:8647214-Mice, pubmed-meshheading:8647214-Mice, Inbred BALB C, pubmed-meshheading:8647214-Mice, Inbred C57BL, pubmed-meshheading:8647214-Neoplasms, Experimental, pubmed-meshheading:8647214-Transfection, pubmed-meshheading:8647214-Tumor Necrosis Factor-alpha, pubmed-meshheading:8647214-Vaccines

Interleukin-12 and B7.1 co-stimulation cooperate in the induction of effective antitumor immunity and therapy of established tumors.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't