Seminars in Immunopathology

, Volume 33, Issue 4, pp 369–383 | Cite as

Immunomodulatory effects of cyclophosphamide and implementations for vaccine design

  • Antonella Sistigu
  • Sophie Viaud
  • Nathalie Chaput
  • Laura Bracci
  • Enrico Proietti
  • Laurence Zitvogel


Drug repositioning refers to the utilization of a known compound in a novel indication underscoring a new mode of action that predicts innovative therapeutic options. Since 1959, alkylating agents, such as the lead compound cyclophosphamide (CTX), have always been conceived, at high dosages, as potent cytotoxic and lymphoablative drugs, indispensable for dose intensity and immunosuppressive regimen in the oncological and internal medicine armamentarium. However, more recent work highlighted the immunostimulatory and/or antiangiogenic effects of low dosing CTX (also called “metronomic CTX”) opening up novel indications in the field of cancer immunotherapy. CTX markedly influences dendritic cell homeostasis and promotes IFN type I secretion, contributing to the induction of antitumor cytotoxic T lymphocytes and/or the proliferation of adoptively transferred T cells, to the polarization of CD4+ T cells into TH1 and/or TH17 lymphocytes eventually affecting the Treg/Teffector ratio in favor of tumor regression. Moreover, CTX has intrinsic “pro-immunogenic” activities on tumor cells, inducing the hallmarks of immunogenic cell death on a variety of tumor types. Fifty years after its Food and Drug Administration approval, CTX remains a safe and affordable compound endowed with multifaceted properties and plethora of clinical indications. Here we review its immunomodulatory effects and advocate why low dosing CTX could be successfully combined to new-generation cancer vaccines.


Cyclophosphamide Chemotherapy Immunotherapy Cancer vaccine Immunomodulation Cancer 


Disclosure of potential conflict of interest

The authors declare no potential conflicts of interest.


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Antonella Sistigu
    • 1
    • 2
    • 3
    • 4
  • Sophie Viaud
    • 1
    • 2
  • Nathalie Chaput
    • 1
    • 2
    • 5
    • 6
  • Laura Bracci
    • 4
  • Enrico Proietti
    • 4
  • Laurence Zitvogel
    • 1
    • 2
    • 3
    • 5
    • 7
  1. 1.INSERM, U1015VillejuifFrance
  2. 2.Institut Gustave RoussyVillejuifFrance
  3. 3.Université Paris-SudVillejuifFrance
  4. 4.Department of Cell Biology and NeurosciencesIstituto Superiore di SanitàRomeItaly
  5. 5.Centre d’Investigation Clinique en Biothérapie, CICBT 507VillejuifFrance
  6. 6.Laboratoire de Thérapie cellulaireInstitut Gustave RoussyVillejuifFrance
  7. 7.U1015 INSERMInstitut Gustave RoussyVillejuif CedexFrance

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