CD8+ T cells activated during the course of murine acute myelogenous leukemia elicit therapeutic responses to late B7 vaccines after cytoreductive treatment

Kyriaki Dunussi-Joannopoulos, Werner Krenger, Howard J. Weinstein, James L M Ferrara, James Croop

Research output: Contribution to journalArticle

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Abstract

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-γ. 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.

Original languageEnglish (US)
Pages (from-to)2915-2924
Number of pages10
JournalBlood
Volume89
Issue number8
StatePublished - Apr 15 1997
Externally publishedYes

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T-cells
Acute Myeloid Leukemia
Vaccines
T-Lymphocytes
Tumors
Leukemia
Chemotherapy
Cytotoxic T-Lymphocytes
Therapeutics
Neoplasms
Cytokines
Combined Vaccines
Drug Therapy
Interferons
Growth
Interleukin-2
Combination Drug Therapy
Assays
Immunosuppression
Chemical activation

ASJC Scopus subject areas

  • Hematology

Cite this

CD8+ T cells activated during the course of murine acute myelogenous leukemia elicit therapeutic responses to late B7 vaccines after cytoreductive treatment. / Dunussi-Joannopoulos, Kyriaki; Krenger, Werner; Weinstein, Howard J.; Ferrara, James L M; Croop, James.

In: Blood, Vol. 89, No. 8, 15.04.1997, p. 2915-2924.

Research output: Contribution to journalArticle

Dunussi-Joannopoulos, Kyriaki ; Krenger, Werner ; Weinstein, Howard J. ; Ferrara, James L M ; Croop, James. / CD8+ T cells activated during the course of murine acute myelogenous leukemia elicit therapeutic responses to late B7 vaccines after cytoreductive treatment. In: Blood. 1997 ; Vol. 89, No. 8. pp. 2915-2924.
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abstract = "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-γ. 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.",
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