Second-Generation Therapeutic DNA Lymphoma Vaccines.

摘要

Lenalidomide is an effective therapeutic agent with direct inhibitory effects on malignant B- and plasma cells and immunomodulatory effects on the T cell activation. The dual function of lenalidomide makes it an appealing candidate for combination with other novel agents for lymphoma and myeloma therapy. In this study, we investigated the immune stimulatory effects of lenalidomide, administrated to mice in doses which provided comparable pharmacokinetics to human patients, on the potency of a novel fusion DNA lymphoma idiotype vaccine. The combination protected mice from lethal challenge with syngeneic A20 murine lymphoma, resulting in significantly improved survival comparing with vaccine or lenalidomide alone and induced immune memory. In vivo depletion experiments demonstrated a requirement for effector CD8+ and CD4+ T cells. Surprisingly, lenalidomide alone was associated with reduced numbers of systemic immune suppressive cells (MDSC/Treg) in tumor-bearing, but not na ve mice, an effect that was independent of tumor burden reduction, suggesting a role of lenalidomide in ameliorating tumor-induced immune suppression. Finally, the combination of lenalidomide and vaccine produced significantly improved survival, compared with controls receiving vaccine or lenalidomide alone in mice with 7 day established tumors. These results demonstrated the dual effect of lenalidomide on enhancing antigen-specific Tcell immunity and a novel mechanism of action reversing tumor immune suppression, which makes it ideal for combination with active specific immunotherapy.