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

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.