Improved efficacy of dendritic cell vaccines and successful immunization with tumor antigen peptide-pulsed peripheral blood mononuclear cells by coadministration of recombinant murine interleukin-12
F. Fallarino et al., Improved efficacy of dendritic cell vaccines and successful immunization with tumor antigen peptide-pulsed peripheral blood mononuclear cells by coadministration of recombinant murine interleukin-12, INT J CANC, 80(2), 1999, pp. 324-333
The well-characterized P815 tumor model was used to optimize anti-tumor imm
unization approaches in mice, Tumor peptides derived from antigens P198 or
PIA were targeted to antigen-presenting cells (APC) by ex vivo pulsing, Ini
tial experiments with irradiated pulsed splenic dendritic cells (sDC) injec
ted weekly in the hind footpads for 3 weeks demonstrated cytolytic T lympho
cyte (CTL) generation in 10-20% of mice. Because of the importance of inter
leukin-12 (IL-12) in tumor rejection responses, pulsed sDCs also were given
together with recombinant murine IL-12 (rmIL-12), This strategy induced pe
ptide-specific CTL in 100% of the mice, The IL-12 had to be injected in the
footpads on days 0, 1 and 2 of each immunization week to achieve an optima
l effect. The improvement seen with the addition of IL-12 prompted examinat
ion of other sources of APC, Purified resting B cells, lipopolysaccharide (
LPS) blasts and non-fractionated splenocytes or peripheral blood mononuclea
r cells (PBMC) were pulsed with peptide and administered with the same sche
dule of rmIL-12, Because these cell types appeared to bind peptides less av
idly than did DC, increasing peptide doses were used during pulsing, Intere
stingly, immunization with each of these APC also induced specific CTL in 1
00% of mice, provided rmIL-12 was coadministered, CTLs were detected both i
n the spleen and in the peripheral blood, Immunization with irradiated, P1A
-pulsed PBMC plus rmIL-12 resulted in protection against challenge with tum
ors expressing the specific antigen in all mice. The ease by which human pa
tient PBMCs can be prepared provides a straightforward vaccination approach
to be used in clinical trials of peptide-based immunization in melanoma. (
C) 1999 Wiley-Liss, Inc.