Intracranial paracrine interleukin-2 therapy stimulates prolonged antitumor immunity that extends outside the central nervous system

Matthew Glaize Ewend, Reid C. Thompson, Richard Anderson, Allen K. Sills, Kevin Staveley-O'Carroll, Betty Mae Tyler, Justin Hanes, Daniel Brat, Matthew Thomas, Elizabeth M. Jaffee, Drew M. Pardoll, Henry Brem

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

To explore the potential efficacy of local cytokine delivery against tumors in the central nervous system (CNS), C57BL6 mice were simultaneously given intracranial injections of tumor challenge and of irradiated B16F10 melanoma cells transduced to secrete interleukin-2 (IL-2). Intracranial IL-2 therapy generated antitumor responses capable of extending the survival of animals that received simultaneous intracranial tumor challenge either locally or at distant sites in the brain. Nontransduced melanoma cells had little effect. Animals that survived intracranial IL-2 therapy and tumor challenge showed prolonged survival compared with controls when challenged with a second tumor dose 70 days after initial treatment. In addition, animals that rejected intracranial tumors were also protected from tumor growth upon rechallenge at sites outside the CNS (i.e., subcutaneous tumor challenge). Conversely, identical or 10-fold larger doses of IL-2-transduced cells administered by subcutaneous injection failed to generate protection against intracranial tumor challenges. Elimination of T-cell and natural killer (NK) subsets using gene knockout mice and antibody-depletion techniques demonstrated that NK cells were most important for the initial antitumor response, whereas CD4+ T-cells were not necessary. These studies demonstrate that local IL-2 therapy in the brain not only generates an immediate local antitumor immune response, but also establishes long-term immunologic memory capable of eliminating subsequent tumor challenges within and outside of the CNS. Furthermore, the antitumor response to paracrine IL-2 in the brain differed significantly from that in the flank, suggesting that the intrinsic CNS cells involved in initiating immunity within the brain have different cytokine requirements from their peripheral counterparts.

Original languageEnglish (US)
Pages (from-to)399
Number of pages1
JournalJournal of Immunotherapy
Volume23
Issue number4
DOIs
StatePublished - 2000

Keywords

  • Brain tumor
  • Immunologic memory
  • Immunotherapy
  • Interleukin-2
  • Melanoma

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

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  • Cite this

    Ewend, M. G., Thompson, R. C., Anderson, R., Sills, A. K., Staveley-O'Carroll, K., Tyler, B. M., Hanes, J., Brat, D., Thomas, M., Jaffee, E. M., Pardoll, D. M., & Brem, H. (2000). Intracranial paracrine interleukin-2 therapy stimulates prolonged antitumor immunity that extends outside the central nervous system. Journal of Immunotherapy, 23(4), 399. https://doi.org/10.1097/00002371-200007000-00007