Gemcitabine enhances antitumor efficacy of recombinant lipoimmunogen-based immunotherapy.

Abstract

Although immunotherapy is an attractive approach for cancer treatment, increasing evidence has shown that the combination of immunotherapy with other treatment modalities may improve the outcome of advanced malignancy. We combined the anticancer drug gemcitabine (Gem) with recombinant lipoprotein-based immunotherapy (rlipo-E7m/CpG) to treat advanced cancer. Mice bearing huge solid tumors (≧ 12 mm in diameter) or orthotopic cervical cancer were treated with a therapeutic regimen consisting of rlipo-E7m/CpG and Gem. In addition, tumor-infiltrating immune cells were quantified by flow cytometry following the chemotherapy and/or immunotherapy. We observed the eradication of huge tumors following the administration of Gem on days 21, 24, and 27 or following rlipo-E7m/CpG therapy on day 30 post-tumor implantation. The combination therapy substantially reduced the number of immunosuppressive cells (CD11b+Gr-1+, CD11b+F4/80+, and CD4+CD25+FOXP3+) and increased the number of tumor-infiltrating antigen-specific CD8+ T cells compared to Gem or rlipo-E7m/CpG monotherapy. Interestingly, the administration of Gem and rlipo-E7m/CpG reduced the quantity of programmed cell death protein 1 (PD-1)-expressing antigen-specific cytotoxic T lymphocytes (CTLs) in the regressing tumors. These findings demonstrated that Gem enhances the eradication of huge tumors by inhibiting a broad range of immunosuppressive cells when combined with immunotherapy. Based on the promising results from this animal study, Gem chemotherapy combined with recombinant lipoimmunogen-based immunotherapy represents a feasible approach for cancer therapy.

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