Activation of NK and NKT Cells

The observed spontaneous tumor regressions seen in episodes of sepsis prompted Coley to test bacterial toxins as a form of immunotherapy. While occasional anti-tumor effects were observed using Bacillus Calmette Guerin in the early 1970s, this "non-specific immune activation" strategy has evolved into the application of highly purified recombinant human cytokines such as IFN-g (Evans et al. 1989), and IL-2 (Handgretinger et al. 1987). As single agents, their anti-tumor effect was modest whether they were used alone (Bauer et al. 1995), or in combination with autologous stem cell transplantation (Favrot et al. 1990; Toren et al. 2000; Bonig et al. 2000; Pession et al. 1998; Marti et al. 1995), despite evidence of immune activation (increase in NK cells, CD8+ cells, and soluble IL-2-Ra) (Vlk et al. 2000). Other NK and NKT-activating cytokines explored in NB therapy include IL-12 (Shimizu et al. 2001), IL-15 (Satoh et al. 1998), and IL-18 (Heuer et al. 1999), as single agents or in combination with IL-2 in murine models (Wigginton and Wiltrout 2002). Dendritic cells have also been used to activate NK cells via CD40 (Valteau-Couanet et al. 2002; Turner et al. 2001). Galactosyl-ceramide is a potent stimulator of NKT cells with potential for clinical applications (Wu et al. 2003; Metelitsa et al. 2001; Smyth et al. 2002). Alternatively, NK/NKT cells can also be gene modified with scFv chimeric immune receptor (CIR) to be redirected to human tumors (Koehne et al. 2003).

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