In vivo administration of systemic IL-2 and IL-12 can result in anti-tumor effects against syngeneic NB tumors and is mediated, at least in part, through CD8+

T cells (Wigginton and Wiltrout 2002; Siapati et al. 2003). Similarly, Flt-3L is a cytokine known to activate APC directly. It can induce NK cell expansion and enhance APC function to provide better specific activation of T cells. Mice bearing weakly immuno-genic NB can develop anti-tumor responses following 10-17 consecutive days of Flt-3L treatment. Following tumor eradication, these animals demonstrate protective T-cell-mediated immunity to tumor re-challenge (Neal et al. 2003). The specific antigens recognized by T cells in these tumor models have not been characterized.

Effective endogenous T-cell expansion and immunization can be induced by direct injection of immune stimulants such as IL-2, GM-CSF, CpG (Sandler et al. 2003), or B7 (Todo et al. 2001) directly into sites of tumor. While this cytokine injection approach for activating T cells has been demonstrated in murine models for other tumors, it has not yet been evaluated for patients with NB. The administration of fusion proteins consisting of monoclonal antibodies linked to cytokines (IL-2 or GM-CSF) may target cytokines to tumor sites and be alternatives to direct intratumor injection of immune stimulants (Davis and Gillies 2003).

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