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

Academic Article
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Overview

authors

  • Zitvogel, L.
  • Robbins, Paul D.
  • Storkus, W. J.
  • Clarke, M. R.
  • Maeurer, M. J.
  • Campbell, R. L.
  • Davis, C. G.
  • Tahara, H.
  • Schreiber, R. D.
  • Lotze, M. T.

publication date

  • June 1996

journal

  • European Journal of Immunology  Journal

abstract

  • 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.

subject areas

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

keywords

  • antitumor immune response
  • co-stimulation
  • cytokine
  • gene therapy
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Identity

International Standard Serial Number (ISSN)

  • 0014-2980

Digital Object Identifier (DOI)

  • 10.1002/eji.1830260624

PubMed ID

  • 8647214
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Additional Document Info

start page

  • 1335

end page

  • 1341

volume

  • 26

issue

  • 6

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