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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
Kyriaki Dunussi-Joannopoulos,
Glenn Dranoff,
Howard J. Weinstein,
James L.M. Ferrara,
Barbara E. Bierer, and
James M. Croop
From the Dana-Farber Cancer Institute and Massachusetts General
Hospital, Harvard Medical School, Boston, MA.
In an attempt to explore novel treatment modalities in acute myeloid
leukemia (AML), we studied the role of costimulatory and cytokine gene
immunotherapy in murine AML. We have previously shown that leukemic
mice 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
immunosuppression induced by tumor growth. CD8+ T cells,
which are necessary for tumor rejection, are activated rather than
suppressed during the first half of the leukemic course in
nonvaccinated mice. In this report, we question whether CD86 (B7.2) or
the cytokines granulocyte-macrophage colony-stimulating factor
(GM-CSF), interleukin-4 (IL-4), or tumor necrosis factor- (TNF-)
can improve the vaccination potential of AML cells. The choice of
cytokines was based on their combined and alone as well ability to
direct the differentiation of CD34+ cells 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- (GM-,
IL-4-, TNF--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--AML cells, can elicit leukemia-specific protective and
therapeutic immunity; and (4) in head-to-head comparison experiments,
vaccination with irradiated GM-AML is more potent than B7.1-AML, curing
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 deserves
clinical evaluation in AML.
Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 222-230
© 1998 by The American Society of Hematology.
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