GENE IMMUNOTHERAPY IN MURINE ACUTE MYELOID-LEUKEMIA - GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR TUMOR-CELL VACCINES ELICIT MORE POTENT ANTITUMOR IMMUNITY COMPARED WITH B7 FAMILY AND OTHER CYTOKINE VACCINES

In an attempt to explore novel treatment modalities in acute myeloid l eukemia (AML), we studied the role of costimulatory and cytokine gene immunotherapy in murine AML. We have previously shown that leukemic mi ce can be cured with CD80 transfected leukemic cells (B7.1-AML vaccine ) administered early in the course of the disease and that the failure B7.1-AML vaccines administered late cannot be attributed to immunosup pression induced by tumor growth, CD8(+) T cells, which are necessary for tumor rejection, are activated rather than suppressed during the f irst half of the leukemic course in nonvaccinated mice. In this report , we question whether CD86 (B7.2) or the cytokines granulocyte-macroph age colony-stimulating factor (GM-CSF), interleukin-4 (IL-4), or tumor necrosis factor-alpha (TNF-alpha) can improve the vaccination potenti al of AML cells. The choice of cytokines was based on their combined a nd alone as well ability to direct the differentiation of CD34(+) cell s into potent antigen-presenting dendritic cells in vitro. Our studies show that (1) mice vaccinated with a leukemogenic number of AML cells engineered to express B7.2 (B7.2-AML) or to secrete GM-CSF, IL-4, or TNF-alpha (GM-, IL-4-, TNF-alpha-AML) do not develop leukemia; (2) GM- AML cells are tumorigenic in sublethally irradiated SJL/J mice but not in Swiss nu/nu mice, indicating that killing of tumor cells is not T- cell-dependent; (3) vaccines with irradiated GM-AML, but not B7.2-, IL -4-, or TNF-alpha-AML cells, can elicit leukemia-specific protective a nd therapeutic immunity; and (4) in head-to-head comparison experiment s, vaccination with irradiated GM-AML is more potent than B7.1-AML, cu ring 80% and providing 20% prolonged survival of the leukemic mice at week 2, as opposed to cures only up to 1 week with B7.1-AML vaccines, These preclinical data emphasize that GM-CSF gene immunotherapy deserv es clinical evaluation in AML. (C) 1998 by The American Society of Hem atology.