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.