Retrovirus-mediated gene transfer of the cytokine genes interleukin-1 betaand tumor necrosis factor-alpha into human neuroblastoma cells: consequences for cell line behavior and immunomodulatory properties

We have investigated the value of a gene therapy approach for neuroblastoma (NB), based on retroviral transduction of the IL-1 beta or TNF-alpha cytok ine genes into human NB lines. Secretion of the corresponding cytokine, was demonstrated in all lines, although with considerable quantitative variati ons. Cytokine gene expression significantly reduced the proliferation index (p = 0.0001); this effect was associated with either terminal neuronal ton e TNF-alpha line) or fibroblast-like differentiation (two IL-1 beta lines), leading to growth arrest after a few weeks. Cell surface levels of CD54 an d HLA class II remained unaffected, but BLA class I (p < 0.001) and CD58 ex pression (p = 0.01) increased on SKNSH after TNF <alpha> gene transfer Mono nuclear cells from normal allogeneic donors cocultured with both IL-1 beta (p < 0.001) and TNF-<alpha> lines (p < 0.01), showed a significant increase in the proportion of activated T cells (CD3(+)DR(+)); however, their cytot oxicity and proliferation rate remained unchanged. Immunotherapy of neurobl astoma will require identification of transduced lines in which cytokine se cretion induces phenotypic changes in such a way as to augment their likely immunomodulatory properties without impeding cell growth. Because of the l imited efficacy of IL-1<beta> or TNF-beta gene transfer alone, further stud ies should focus on combination with other immunomodulatory agents, to impr ove their potential efficacy in neuroblastoma.