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

Miki Tongu, Nanae Harashima, Koji Tamada, Lieping Chen, Mamoru Harada

Research output: Contribution to journalArticlepeer-review

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-1high/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. Intermittent chemotherapy and anti-CD137 antibody therapy.

Original languageEnglish (US)
Pages (from-to)9-17
Number of pages9
JournalCancer Science
Volume106
Issue number1
DOIs
StatePublished - Jan 1 2015

Keywords

  • Antibody
  • CD137
  • Cyclophosphamide
  • Gemcitabine
  • Myeloid-derived suppressor cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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