IMMUNOTHERAPY VIA GENE-THERAPY - COMPARISON OF THE EFFECTS OF TUMOR-CELLS TRANSDUCED WITH THE INTERLEUKIN-2, INTERLEUKIN-6, OR INTERFERON-GAMMA GENES

We have comparatively analyzed the immune mechanisms induced by and th e immunotherapeutic potentials of a highly metastatic clone of the Lew is lung carcinoma, D122, transduced with the interleukin-2 (IL-2), IL- 6, or interferon-gamma (IFN-gamma) genes. All of the D122 cytokine gen e-transduced cells induced antitumor CD8+ cytotoxic T lymphocytes (CTL s), as can be judged from in vivo depletion of CD8+ cells and in vitro CTL assays. In vivo depletion of CD4+ cells did not affect the malign ant phenotypes of the different D122 gene-modified cells, but in vivo depletion of natural killer (NK) cells resulted in increased malignanc y of both D122 cells and D122 gene-modified cells. In accordance with the effects of in vivo NK depletion, D122 as well as D122 derivative c ells were sensitive to lysis by polyinosinic-polycytidylic acid (poly I:C)-induced activity. We discuss the immune responses generated by th e different D122 gene-modified cells in view of their in vivo behavior in syngeneic and nude mice. We also performed comparative analysis of the capacity of vaccinations with irradiated D122 gene-modified cells to cure established micrometastases of parental D122 cells in tumor-o perated mice. Vaccinations with D122-IL-2 or -IL-6 secretors did not g enerate a significant effect. Also, vaccinations with D122-IFN-gamma c ells, which showed increased major histocompatibility complex class I expression but did not secrete detectable levels of IFN-gamma, did not cure established micrometastases. Only vaccination with D122-IFN-gamm a high secretors efficiently cured postoperated mice carrying establis hed micrometastases. We discuss the relevance of these results to the application of immunotherapy via cytokine gene therapy of human malign ancy.