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CD8+ T cells activated during the course of murine acute myelogenous
leukemia elicit therapeutic responses to late B7 vaccines after
cytoreductive treatment
K Dunussi-Joannopoulos, W Krenger, HJ Weinstein, JL Ferrara and JM Croop
Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
02115, USA.
We have previously shown in a murine acute myelogenous leukemia (AML) model
that leukemic mice can be cured with a B7 vaccine if immunized early in the
disease and that CD8+ T cells are necessary for tumor rejection. However,
when B7 vaccine is administered 2 weeks after leukemia inoculation, the
effect is only prolonged survival, ending in death virtually of all the
mice. To distinguish between tumor kinetics and tumor-induced
immunosuppression as potential mechanisms eliminating the therapeutic
potential of late B7 vaccines, we performed in vitro T- cell studies during
leukemia progression and in vivo studies on the clinical outcome of late B7
vaccines in combination with prior cytoreductive chemotherapy. Our results
show that CD8+ T cells from leukemic mice 1 and 2 weeks after leukemia
inoculation proliferate more vigorously in response to in vitro activation
than cells from normal mice and produce Th1-type cytokines interleukin-2
and interferon-gamma. Cytotoxic T lymphocyte (CTL) assays demonstrate that
cells from week-2 vaccinated mice (which succumb to their leukemia),
surprisingly develop a stronger CTL activity than cells from week-1
vaccinated mice (which reject their leukemia). Finally, the combination of
late chemotherapy and late B7 vaccine administration can cure only 20% of
leukemic mice, whereas early chemotherapy and the same late B7 vaccine
administration cure 100% of leukemic mice. These results demonstrate that
in murine AML tumor growth does not induce T-cell anergy or a Th2 cytokine
profile and suggest that tumor growth is most likely to be the limiting
factor in the curative potential of late B7 vaccines.
Volume 89,
Issue 8,
pp. 2915-2924,
04/15/1997
Copyright © 1997 by The American Society of Hematology
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