title: Intermittent chemotherapy can retain the therapeutic potential of anti-CD137 antibody during the late tumor-bearing state.
abstract: Immunomodulating monoclonal antibodies (mAb) can evoke antitumor T-cell responses, which are attenuated by regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). Treatment with cyclophosphamide (CP) and gemcitabine (GEM) can mitigate the immunosuppression by Treg and MDSC, respectively. In the current study, we examined the antitumor effects of a combination of local injection with anti-CD137 mAb and intermittent low-dose chemotherapy using CP and GEM in subcutaneously established CT26 colon carcinoma. Although a significant antitumor effect was observed when local anti-CD137 mAb therapy (5 μg) was started early in the tumor-bearing stage (day 10), no therapeutic efficacy was observed when the mAb therapy was started at a later tumor-bearing stage (day 17). Analyses of the tumor-infiltrating immune cells revealed that the number of Gr-1(high/low) CD11b(+) MDSC started to increase 13 days after tumor inoculation, whereas injection with low-dose (50 mg/kg) CP and GEM mitigated this increase. In addition, although intermittent injections with low-dose CP and GEM on days 10 and 18 suppressed tumor growth significantly, additional local injections of anti-CD137 mAb on days 19, 21, and 23 further augmented the therapeutic efficacy. Cytotoxic T lymphocytes reactive to CT26 and a tumor antigen peptide were induced successfully from the spleen cells of tumor-cured or tumor-stable mice. In a bilateral tumor inoculation model, this combination therapy achieved systemic therapeutic effects and suppressed the growth of mAb-untreated tumors. These results suggest that intermittent immunochemotherapy using CP and GEM could retain the therapeutic potential of anti-CD137 mAb that is normally impaired during the late tumor-bearing stage.
authors.affiliation: Department of Experimental Animals, Center for Integrated Research in Science, Shimane University, Izumo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Tongu
authors.forename: Nanae
authors.initials: N
authors.lastname: Harashima
authors.forename: Koji
authors.initials: K
authors.lastname: Tamada
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Mamoru
authors.initials: M
authors.lastname: Harada
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000920:Antibody-Dependent Cell Cytotoxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004354:Drug Screening Assays, Antitumor; D005260:Female; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D022423:Myeloid Cells / Q000276:immunology; D009368:Neoplasm Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D047368:Tumor Burden / Q000187:drug effects; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D003841:Deoxycytidine; D003520:Cyclophosphamide; D000093542:Gemcitabine
keywords: Antibody; CD137; cyclophosphamide; gemcitabine; myeloid-derived suppressor cells