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Immunomodulatory effects of cyclophosphamide and implementations for vaccine design

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Abstract

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.

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Authors and Affiliations

  1. INSERM, U1015, 94805, Villejuif, France

    Antonella Sistigu, Sophie Viaud, Nathalie Chaput & Laurence Zitvogel

  2. Institut Gustave Roussy, 94805, Villejuif, France

    Antonella Sistigu, Sophie Viaud, Nathalie Chaput & Laurence Zitvogel

  3. Université Paris-Sud, 94805, Villejuif, France

    Antonella Sistigu & Laurence Zitvogel

  4. Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161, Rome, Italy

    Antonella Sistigu, Laura Bracci & Enrico Proietti

  5. Centre d’Investigation Clinique en Biothérapie, CICBT 507, 94805, Villejuif, France

    Nathalie Chaput & Laurence Zitvogel

  6. Laboratoire de Thérapie cellulaire, Institut Gustave Roussy, 94805, Villejuif, France

    Nathalie Chaput

  7. U1015 INSERM, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France

    Laurence Zitvogel

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  1. Antonella Sistigu
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This article is published as part of the Special Issue on Prognostic Impact of Anti-Cancer Immune Responses

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Sistigu, A., Viaud, S., Chaput, N. et al. Immunomodulatory effects of cyclophosphamide and implementations for vaccine design. Semin Immunopathol 33, 369–383 (2011). https://doi.org/10.1007/s00281-011-0245-0

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