Intermittent chemotherapy can retain the therapeutic potential of anti-CD137 antibody during the late tumor-bearing state

Cancer Sci. 2015 Jan;106(1):9-17. doi: 10.1111/cas.12568. Epub 2014 Dec 9.

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.

Keywords: Antibody; CD137; cyclophosphamide; gemcitabine; myeloid-derived suppressor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibody-Dependent Cell Cytotoxicity*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cyclophosphamide / administration & dosage
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Drug Screening Assays, Antitumor
  • Female
  • Gemcitabine
  • Mice, Inbred BALB C
  • Mice, Nude
  • Myeloid Cells / immunology
  • Neoplasm Transplantation
  • T-Lymphocytes, Cytotoxic / immunology
  • Tumor Burden / drug effects
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology

Substances

  • Antibodies, Monoclonal
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Deoxycytidine
  • Cyclophosphamide
  • Gemcitabine