Effect of irradiation on cytokine production, MHC antigen expression, and vaccine potential of interleukin-2 and interferon-gamma gene-modified melanoma cells.
Recent studies have shown that tumor cells transduced with interleukin-2 (IL-2) or interferon-gamma (IFN-gamma) genes stimulated a potent and specific antitumor immunity in experimental animals. For use as a human vaccine, tumor cells must be inactivated by irradiation to ensure the arrest of their growth. This study was undertaken to examine the effects of irradiation (10,000 rad) on the growth characteristics and vaccine potential of IL-2 and IFN-gamma-modified human melanomas and B16 murine melanoma. Irradiation caused cessation of cell growth and gradual reduction of cell number. Irradiated melanoma cells displayed 1.5 to 10-fold increases in the surface expression of MHC class I and/or class II antigens. The increases in MHC antigens persisted for 7-14 days postirradiation and then declined thereafter. Furthermore, IL-2- and IFN-gamma-transduced melanoma cells showed enhanced expression of the cytokine mRNA and increased cytokine secretion after irradiation. The effect of irradiation on the vaccine potential of the transduced cells was examined in C57BL/ 6 mice by prophylactic immunization and immunotherapy, and in nude mice by mixed transplantation assays. The irradiated, cytokine-transduced B16 cell vaccine was as or more effective than the unirradiated vaccine. These irradiated vaccines protected the animals against a challenging tumorigenic dose of B16 parental cells and suppressed the growth of 4-day-established B16 lung metastases. The ability of the irradiated IL-2-transduced human melanomas to inhibit the growth of admixed parental melanoma cells was retained but was less efficacious than unirradiated cells. The results suggest that irradiation does not abrogate the vaccine potential of IL-2- and IFN-gamma-transduced melanomas. These findings have implications for designing specific active immunotherapy protocols utilizing cytokine gene-modified tumor cells.
Abdel-Wahab, Z; Dar, MM; Hester, D; Vervaert, C; Gangavalli, R; Barber, J; Darrow, TL; Seigler, HF
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