Document Detail


Vaccines with interleukin-12-transduced acute myeloid leukemia cells elicit very potent therapeutic and long-lasting protective immunity.
MedLine Citation:
PMID:  10590071     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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-gamma (IFN-gamma), 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-gamma 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. (51)Cr 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.
Authors:
K Dunussi-Joannopoulos; K Runyon; J Erickson; R G Schaub; R G Hawley; J P Leonard
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Blood     Volume:  94     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  1999 Dec 
Date Detail:
Created Date:  2000-01-10     Completed Date:  2000-01-10     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  4263-73     Citation Subset:  AIM; IM    
Affiliation:
Department of Preclinical Research, Genetics Institute, Andover, MA, USA.
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MeSH Terms
Descriptor/Qualifier:
Acute Disease
Animals
Cancer Vaccines* / administration & dosage,  immunology
Cross Reactions
Cytotoxicity, Immunologic*
Epitopes / immunology
Gene Transfer Techniques
Hematopoietic Stem Cells / immunology
Interleukin-12 / administration & dosage,  genetics,  immunology*
Leukemia, Experimental / immunology*,  prevention & control
Leukemia, Myeloid / immunology*
Mice
Recombinant Proteins / administration & dosage,  genetics,  immunology
Chemical
Reg. No./Substance:
0/Cancer Vaccines; 0/Epitopes; 0/Recombinant Proteins; 187348-17-0/Interleukin-12

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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