There is an urgent need to develop targeted
therapies for the control of advanced stage
ovarian cancer because it is the most deadly gynecologic
cancer.
Antigen-specific
immunotherapy is a promising approach because of the potential of the immune system to specifically target
tumors without the toxicity associated with traditional chemoradiation. However, one of the major limitations for
antigen-specific
cancer immunotherapy is the pre-existing immune tolerance against endogenous targeted
tumor antigens that frequently evolves during
carcinogenesis. Here, we described the creation of a therapeutic agent comprised of a
tumor-homing module fused to a functional domain capable of selectively rendering
tumor cells sensitive to foreign
antigen-specific CD8+ T cell-mediated immune attack, thereby circumventing many aspects of immune tolerance. The
tumor-homing module, NKG2D, specifically binds to NKG2D
ligand that is commonly overexpressed in ovarian
tumors. The functional domain is comprised of the Fc portion of
IgG2a protein and foreign immunogenic CD8+
T cell epitope flanked by
furin cleavage sites (R), which can be recognized and cleaved by
furin that is highly expressed in the tumor microenvironment.
RESULTS: We show that this therapeutic chimeric
protein specifically loaded antigenic
epitope onto the surface of NKG2D
ligand-expressing ovarian
tumor cells, rendering ovarian
tumors susceptible to
antigen-specific CTL-mediated killing in vitro. Furthermore, we show that intraperitoneal administration of our therapeutic chimeric
protein followed by adoptive transfer of
antigen-specific CD8+ T cells generates potent antitumor effects and significant accumulation of
antigen-specific CD8+ T cells in the
tumor loci.
CONCLUSIONS: