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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-04-1063.
Submitted April 5, 2002
Accepted July 15, 2002
Comparative analysis of murine marrow-derived dendritic cells generated by Flt3L or GM-CSF/IL4 and matured with immune stimulatory agents on the in vivo induction of anti-leukemia responses
Brenda J Weigel*, Narender Nath, Patricia A Taylor, Angela Panoskaltsis-Mortari, Wei Chen, Arthur M Krieg, Kenneth Brasel, and Bruce R Blazar
Department of Pediatrics, Division of Pediatric Hematology/Oncology and Blood & Marrow Transplant, University of Minnesota Cancer Center, Minneapolis, MN, USA
Department of Veteran Affairs Medical Center and the Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA, USA
Departments of Immunobiology and Discovery Research, Immunex Corp., Seattle, WA, USA
* Corresponding author; email: weige007{at}tc.umn.edu.
Bone marrow (BM)-derived dendritic cells (DCs) cultured in GM-CSF and IL-4 have been used to generate anti-tumor immune responses. The cytokine Flt3L also has been shown to generate BM DCs. We sought to determine if DCs generated using Flt3L then matured with LPS could lead to DCs with in vivo anti-AML activity. Lipopolysaccharide (LPS) and TNF- are effective agents for maturing DCs, however, they have potential in vivo toxicities. CpG oligodeoxynucleotides (CpGs) are considered relatively non-toxic, potent activators of DC function and maturation in vitro and in vivo. We investigated whether CpGs would be comparable to TNF or LPS for the maturation of GM-CSF/IL4 generated DCs. DCs cultured with GM-CSF/IL-4 and matured with TNF-, LPS- or CpG produced a greater allogeneic T-cell response compared to Flt3L/LPS-generated DCs. All 4 distinct DC types pulsed with AML-lysate and administered before tumor challenge produced an increase in the total number of splenic anti-AML specific cytotoxic T-lymphocyte precursors and led to significantly improved survival compared to non-vaccinated controls. GM-CSF/IL-4/LPS was superior to Flt3L/LPS for generating anti-AML effects in vivo. Whereas TNF was comparable to LPS in conferring upon GM-CSF/IL-4 DCs anti-AML effects in vivo, CpGs were superior to LPS. These data have important clinical implications and are the first to show that Flt3L-generated DCs can provide anti-tumor protection and that non-toxic agents such as CpGs and Flt3L may be useful in the clinical development of DC vaccines.
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