Immunological effects of low-dose cyclophosphamide in cancer patients treated with oncolytic adenovirus

Mol Ther. 2011 Sep;19(9):1737-46. doi: 10.1038/mt.2011.113. Epub 2011 Jun 14.


Patients with advanced solid tumors refractory to and progressing after conventional therapies were treated with three different regimens of low-dose cyclophosphamide (CP) in combination with oncolytic adenovirus. CP was given with oral metronomic dosing (50 mg/day, N = 21), intravenously (single 1,000 mg dose, N = 7) or both (N = 7). Virus was injected intratumorally. Controls (N = 8) received virus without CP. Treatments were well tolerated and safe regardless of schedule. Antibody formation and virus replication were not affected by CP. Metronomic CP (oral and oral + intravenous schedules) decreased regulatory T cells (T(regs)) without compromising induction of antitumor or antiviral T-cell responses. Oncolytic adenovirus given together with metronomic CP increased cytotoxic T cells and induced Th1 type immunity on a systemic level in most patients. All CP regimens resulted in higher rates of disease control than virus only (all P < 0.0001) and the best progression-free (PFS) and overall survival (OS) was seen in the oral + intravenous group. One year PFS and OS were 53 and 42% (P = 0.0016 and P < 0.02 versus virus only), respectively, both which are unusually high for chemotherapy refractory patients. We conclude that low-dose CP results in immunological effects appealing for oncolytic virotherapy. While these first-in-human data suggest good safety, intriguing efficacy and extended survival, the results should be confirmed in a randomized trial.

Publication types

  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Adolescent
  • Adult
  • Aged
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Child
  • Combined Modality Therapy
  • Cricetinae
  • Cyclophosphamide / administration & dosage*
  • Cyclophosphamide / immunology
  • Cyclophosphamide / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Genetic Vectors
  • Humans
  • Male
  • Mesocricetus
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Oncolytic Virotherapy / methods*
  • T-Lymphocytes, Regulatory / immunology*
  • Treatment Outcome
  • Young Adult


  • Antineoplastic Agents
  • Cyclophosphamide