Vaccines with interleukin-12-transduced acute myeloid leukemia cells elicit very potent therapeutic and long-lasting protective immunity

Interleukin-12 (IL-12) is a heterodimeric cytokine mediating a dynamic inte rplay between T cells and antigen-presenting cells (APCs), Preclinical stud ies have demonstrated that recombinant murine IL-12 (rmIL-12) promotes spec ific antitumor immunity mediated by T cells in several types of tumors. How ever, 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 b ut is incapable of rescuing mice from lethal leukemia. In contrast, AML cel ls genetically modified to express IL-12 (IL12-AML) using murine stem cell virus (MSCV) p40 + p35 elicit very potent antileukemic activity. Vaccines w ith lethally irradiated IL12-AML cells protect naive mice against challenge with wild-type AML cells and, more importantly, can cure mice bearing a co nsiderable leukemic burden. Immunized mice show no signs of systemic IL-12 toxicity and their spleen histology is comparable with naive mice spleen. I n vivo depletion of IL-12, interferon-gamma (IFN-gamma), or CD8(+) T cells after injections with live IL12-AML cells abrogates completely the antileuk emia 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 B 7.1 and B7.2, but no significant direct antiproliferative effect. Cr-51 rel ease assays show that rejection of live IL12-AML cells supports the develop ment of long-lasting leukemia-specific cytotoxic T lymphocyte (CTL) activit y. In conclusion, our results demonstrate that IL1Z-AML vaccination is a sa fe and potent immunotherapeutic approach that has a great potential to elim inate minimal residual disease in patients with AML. (C) 1999 by The Americ an Society of Hematology.