Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms

Mikayel Mkrtichyan, Yana G. Najjar, Estella C. Raulfs, Maher Y. Abdalla, Raed Samara, Rinat Rotem-Yehudar, Larry Cook, Samir N. Khleif

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

Programmed death-1 receptor (PD-1) is expressed on T cells following TCR activation. Binding of this receptor to its cognate ligands, programmed death ligand (PDL)-1 and PDL-2, down-regulates signals by the TCR, promoting T-cell anergy and apoptosis, thus leading to immune suppression. Here, we find that using an anti-PD-1 antibody (CT-011) with Treg-cell depletion by low-dose cyclophosphamide (CPM), combined with a tumor vaccine, induces synergistic antigen-specific immune responses and reveals novel activities of each agent in this combination. This strategy led to complete regression of established tumors in a significant percentage of treated animals, with survival prolongation. We show for the first time that combining CT-011 and CPM significantly increases the number of vaccine-induced tumor-infiltrating CD8 + T cells, with simultaneous decrease in infiltrating Treg cells. Interestingly, we find that CT-011 prolongs Treg-cell inhibition induced by CPM, leading to a sustainable significant synergistic decrease of splenic and tumor-infiltrated Treg cells. Surprisingly, we find that the anti-tumor effect elicited by the combination of CT-011 and CPM is dependent on both CD8 + and CD4 + T-cell responses, although the antigen we used is a class I MHC-restricted peptide. Thus, we describe a novel and effective therapeutic approach by combining multiple strategies to target several tumor-mediated immune inhibitory mechanisms.

Original languageEnglish (US)
Pages (from-to)2977-2986
Number of pages10
JournalEuropean Journal of Immunology
Volume41
Issue number10
DOIs
Publication statusPublished - Oct 1 2011

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Keywords

  • Cancer immunotherapy
  • Programmed death-1 receptor
  • Vaccine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Mkrtichyan, M., Najjar, Y. G., Raulfs, E. C., Abdalla, M. Y., Samara, R., Rotem-Yehudar, R., ... Khleif, S. N. (2011). Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms. European Journal of Immunology, 41(10), 2977-2986. https://doi.org/10.1002/eji.201141639