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

97 Citations (Scopus)

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
StatePublished - Oct 1 2011

Fingerprint

Death Domain Receptors
Cancer Vaccines
Regulatory T-Lymphocytes
Cyclophosphamide
T-Lymphocytes
Ligands
Neoplasms
Histocompatibility Antigens Class II
Down-Regulation
Apoptosis
Antigens
Peptides
Antibodies
Therapeutics

Keywords

  • Cancer immunotherapy
  • Programmed death-1 receptor
  • Vaccine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms. / Mkrtichyan, Mikayel; Najjar, Yana G.; Raulfs, Estella C.; Abdalla, Maher Y; Samara, Raed; Rotem-Yehudar, Rinat; Cook, Larry; Khleif, Samir N.

In: European Journal of Immunology, Vol. 41, No. 10, 01.10.2011, p. 2977-2986.

Research output: Contribution to journalArticle

Mkrtichyan, M, Najjar, YG, Raulfs, EC, Abdalla, MY, Samara, R, Rotem-Yehudar, R, Cook, L & Khleif, SN 2011, 'Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms', European Journal of Immunology, vol. 41, no. 10, pp. 2977-2986. https://doi.org/10.1002/eji.201141639
Mkrtichyan, Mikayel ; Najjar, Yana G. ; Raulfs, Estella C. ; Abdalla, Maher Y ; Samara, Raed ; Rotem-Yehudar, Rinat ; Cook, Larry ; Khleif, Samir N. / Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms. In: European Journal of Immunology. 2011 ; Vol. 41, No. 10. pp. 2977-2986.
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