Tumor vaccines expressing flt3 ligand synergize with ctla-4 blockade to reject preimplanted tumors.

摘要: The transformation of a healthy cell into malignant neoplasm involves numerous genetic mutations and aberrations in gene expression. As few these changes are shared between individuals or types cancer, the best source for eliciting broad-spectrum tumor immunity remains each patient's own tumor. Previously, we have shown that combining blockade T-cell-negative costimulatory molecule CTL-associated antigen 4 (CTLA-4) vaccination with irradiated B16 expressing granulocyte macrophage colony-stimulating factor (GM-CSF; Gvax) promotes rejection established murine melanomas. Here show that, like GM-CSF, cytokine Flt3 ligand (Flt3L) expressed coupled CTLA-4 both prophylactic therapeutic B16. When administered at site growing tumor, Gvax fails to prevent outgrowth any mice, whereas B16-Flt3L vaccine (Fl3vax) induces 75% melanomas implanted 3 days before vaccination. Relative Gvax, Fl3vax greater infiltration by CD8+ T cells "sentinel" plasmacytoid dendritic cells. did not synergize when used combination treating melanoma even context CD25+ regulatory T-cell depletion. Further, Flt3L expression can also promote TRAMP prostate adenocarcinomas, proving utility this treatment extends beyond melanoma. Engineering be constitutively secreted attaching an IgG2a tail yielded combined blockade, prevented significantly more 5-day B16-BL6 tumors than Gvax.