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Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4263-4273
Vaccines With Interleukin-12-Transduced Acute Myeloid Leukemia Cells
Elicit Very Potent Therapeutic and Long-Lasting Protective Immunity
Kyriaki Dunussi-Joannopoulos,
Kathlene Runyon,
Jamie Erickson,
Robert G. Schaub,
Robert G. Hawley, and
John P. Leonard
From the Department of Preclinical Research and Development, Genetics
Institute, Andover, MA; and the Hematopoiesis Department, Holland
Laboratory, American Red Cross, Rockville, MD.
Interleukin-12 (IL-12) is a heterodimeric cytokine mediating a
dynamic interplay between T cells and antigen-presenting cells (APCs).
Preclinical studies have demonstrated that recombinant murine IL-12
(rmIL-12) promotes specific antitumor immunity mediated by T cells in
several types of tumors. However, the in vivo antitumor properties of
IL-12 in acute myeloid leukemia (AML) have not been previously
reported. We show here in a murine AML model that systemic administration of rmIL-12 significantly delays tumor growth but is
incapable of rescuing mice from lethal leukemia. In contrast, AML cells
genetically modified to express IL-12 (IL12-AML) using murine stem cell
virus (MSCV) p40 + p35 elicit very potent antileukemic activity.
Vaccines with lethally irradiated IL12-AML cells protect naive mice
against challenge with wild-type AML cells and, more importantly, can cure mice bearing a considerable leukemic burden. Immunized mice show no signs of systemic IL-12 toxicity and their spleen histology is comparable with naive mice spleen. In vivo depletion of IL-12, interferon- (IFN-), or CD8+ T
cells after injections with live IL12-AML cells abrogates completely the antileukemia immune responses. Studies on the in vitro effects of
IFN- on AML cells demonstrate enhanced expression of major histocompatibility complex (MHC) and accessory molecules
and induction of the costimulatory molecules B7.1 and B7.2, but no
significant direct antiproliferative effect. 51Cr release
assays show that rejection of live IL12-AML cells supports the
development of long-lasting leukemia-specific cytotoxic T lymphocyte
(CTL) activity. In conclusion, our results demonstrate that IL12-AML vaccination is a safe and potent immunotherapeutic approach that has a great potential to eliminate minimal residual disease in patients with AML.
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