Vaccination with syngeneic, lymphoma-derived immunoglobulin idiotype combined with granulocyte/macrophage colony-stimulating factor primes mice for a protective T-cell response.

Abstract

The idiotype of the Ig expressed by a B-cell malignancy (Id) can serve as a unique tumor-specific antigen and as a model for cancer vaccine development. In murine models of Id vaccination, formulation of syngeneic Id with carrier proteins or adjuvants induces an anti-idiotypic antibody response. However, inducing a potent cell-mediated response to this weak antigen instead would be highly desirable. In the 38C13 lymphoma model, we observed that low doses of free granulocyte/macrophage colony-stimulating factor (GM-CSF) 10,000 units i.p. or locally s.c. daily for 4 days significantly enhanced protective antitumor immunity induced by s.c. Id-keyhole limpet hemocyanin (KLH) immunization. This effect was critically dependent upon effector CD4+ and CD8+ T cells and was not associated with any increased anti-idiotypic antibody production. Lymphocytes from spleens and draining lymph nodes of mice primed with Id-KLH plus GM-CSF, but not with Id-KLH alone, demonstrated significant proliferation to Id in vitro without any biased production of interferon 'y or interleukin 4 protein or mRNA. As a further demonstration of potency, 50% of mice immunized with Id-KLH plus GM-CSF on the same day as challenge with a large s.c. tumor inoculum remained tumorfree at day 80, compared with 17% for Id-KLH alone, when immunization was combined with cyclophosphamide. Taken together, these results demonstrate that GM-CSF can significantly enhance the immunogenicity of a defined self-antigen and that this effect is mediated exclusively by activating the T-cell arm of the immune response.

Combining a Recombinant Cancer Vaccine with Standard Definitive Radiotherapy in Patients with Localized Prostate Cancer

“…All vaccines were given on day 2 of each 28-day cycle with sargramostim [granulocyte-macrophage colony-stimulating factor (GM-CSF)] 100 Ag/d given s.c. at the same site as the vaccination on days 1 to 4 and aldesleukin (IL-2) 4 MIU/M 2 given s.c. in the abdomen on days 8 to 12. The dose and schedule of GM-CSF and IL-2 were based on previous preclinical and clinical studies (12,13,25,26). GM-CSF has been shown to increase recruitment of dendritic cells and enhance clinical responses to vaccine.…”

Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma

“…Disadvantages are uncertainty over the amount of cytokine reaching the immunization site, the difficulty in maintaining critical levels of cytokine, and the toxicity, albeit modest, associated with systemic administration. In a preclinical immunoprophylaxis model (38C13 lymphoma, C3H/HeN female mice), Kwak et al 14 achieved success with systemically administered GM-CSF. However, s.c. administration at the immunization site was more effective in inducing protection.…”

Characterization of the MUC1.Tg/MIN transgenic mouse as a model for studying antigen-specific immunotherapy of adenomas

“…The MHC class I peptides confer MUC1 specificity leading to the induction of CTL-mediated anti-tumor responses; the Hepatitis B core antigen-derived MHC class II pan T helper peptide was included to boost CD8 + anti-tumor responses [30,31]; CpG-ODN was included to promote DC activation via its interaction with Toll-like receptor (TLR)-9 [32,33] to enhance CTL responses, expansion and survival [33][34][35][36][37]. GM-CSF promotes antigen presentation and DC recruitment to vaccine sites [38][39][40][41] and is commonly used as a biological adjuvant in preclinical and clinical immunotherapy studies [42,43]. In separate experiments, groups of MUC1.Tg/MIN and MIN mice were immunized with the peptide-based vaccine (peptides + CpG-ODN + GM-CSF) or the non-peptide-based vaccine (CpG-ODN + GM-CSF) on day 66 when the mice harbored large numbers of adenomas.…”