Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines

Abstract

The current studies evaluate granulocyte-macrophage colony-stimulating factor (GM-CSF) as a vaccine adjuvant. An important issue for developing vaccine therapy for human malignancy is identifying adjuvants that can elicit T-cell responses to proteins and peptides derived from “self” tumor antigens. GM-CSF, in vitro, stimulates the growth of antigen-presenting cells such as dendritic cells and macrophages. Initial experiments examined whether GM-CSF injected into the skin of rats could affect the number or character of antigen presenting cells, measured as class II major histocompatability complex expressing cells, in lymph nodes draining the injection site. Intradermal (id) inoculation of GM-CSF every 24 hours for a total of five inoculations resulted in an increase of class II+ fluorescing cells that peaked at the fourth inoculation. Subcutaneous (sq) inoculation resulted in an increase of class II+ fluorescing cells that peaked following the second inoculation, then decreased over time. Using this schema for “conditioning” the inoculation site, GM-CSF was administered id or sq for five injections and a foreign antigen, tetanus toxoid (tt), was given at the beginning or the end of the immunization cycle. Id immunization was more effective than sq at eliciting tt specific immunity. In addition, GM-CSF id, administered as a single dose with antigen, compared favorably with complete Freund's adjuvant (CFA) and alum in eliciting tt specific antibody and cellular immunity. We have shown that immunity to rat neu (c-erbB-2) protein, an oncogenic self protein, can be generated in rats by immunization with peptides derived from the normal rat neu sequence plus CFA. The current study demonstrates that rat neu peptides inoculated with GM-CSF could elicit a strong delayed type hypersensitivity reaction (DTH) response, whereas peptides alone were non-immunogenic. GM-CSF was as effective as CFA in generating rat neu specific DTH responses after immunization with a neu peptide based vaccine. Soluble GM-CSF is a potent adjuvant for the generation of immune responses to foreign proteins as well as peptides derived from a self tumor antigen.

Activities of granulocyte‐macrophage colony‐stimulating factor and interleukin‐3 on monocytes

“…Clinical trials confirmed the effectiveness of GM-CSF as a vaccine adjuvant for immune responses to vaccination in case of human tumors [9]. Although immunization with tumor-antigen derived peptides did not induce immune responses, the concomitant administration of GM-CSF elicited delayed type hypersensitivity and T-cell responses [30,31]. The potential of GM-CSF to support the differentiation of monocytes into DCs as a single factor may at least in part be involved in enhancement of the immunological effects induced by the vaccine.…”

Humoral immune responses in patients vaccinated with 1–146 HER2 protein complexed with cholesteryl pullulan nanogel

“…In rat models, serial administration of GM-CSF augmented antigen-specific antibody and cellular responses both for non-self antigen and self antigen HER2 peptides. (21) In a previous clinical trial, Jäger were the first group to report that coadministration of GM-CSF with melanoma-antigen peptide vaccine enhanced peptidespecific immune responses and supported cytotoxic T lymphocyte (CTL)-mediated tumor rejection. (22) Moreover, a randomized phase II trial compared the response to vaccination using gp100 and tyrosinase peptides in an emulsion with GM-CSF to that of peptide-pulsed monocyte-derived dendritic cells.…”

Vaccination of multiple myeloma patients with idiotype‐pulsed dendritic cells: immunological and clinical aspects

“…Furthermore, GM-CSF is involved in the maturation of DCs. Initial experiments by Disis et al (1996) demonstrated that repeated injections of GM-CSF into the skin of rats resulted in an increase in MHC class II 1 cells. On the other hand, growth-stimulating effects of GM-CSF on human myeloma cells have been described in vitro (Zhang et al, 1990), an observation that might be strengthened by the findings of Celsing et al (1992) who reported on the extramedullary progression of MM after GM-CSF treatment.…”