OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis Journal Article

Authors: Hirschhorn-Cymerman, D.; Rizzuto, G. A.; Merghoub, T.; Cohen, A. D.; Avogadri, F.; Lesokhin, A. M.; Weinberg, A. D.; Wolchok, J. D.; Houghton, A. N.
Article Title: OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis
Abstract: Expansion and recruitment of CD4<sup>+</sup> Foxp3<sup>+</sup> regulatory T (T reg) cells are mechanisms used by growing tumors to evade immune elimination. In addition to expansion of effector T cells, successful therapeutic interventions may require reduction of T reg cells within the tumor microenvironment. We report that the combined use of the alkylating agent cyclophosphamide (CTX) and an agonist antibody targeting the co-stimulatory receptor OX40 (OX86) provides potent antitumor immunity capable of regressing established, poorly immunogenic B16 melanoma tumors. CTX administration resulted in tumor antigen release, which after OX86 treatment significantly enhanced the antitumor T cell response. We demonstrated that T reg cells are an important cellular target of the combination therapy. Paradoxically, the combination therapy led to an expansion of T reg cells in the periphery. In the tumor, however, the combination therapy induced a profound T reg cell depletion that was accompanied by an influx of effector CD8<sup>+</sup> T cells leading to a favorable T effector/ T reg cell ratio. Closer examination revealed that diminished intratumoral T reg cell levels resulted from hyperactivation and T reg cell-specific apoptosis. Thus, we propose that CTX and OX40 engagement represents a novel and rational chemoimmunotherapy. © 2009 Hirschhorn-Cymerman et al.
Keywords: controlled study; unclassified drug; cancer combination chemotherapy; drug potentiation; nonhuman; antineoplastic agents; antigen expression; cd8+ t lymphocyte; cd8-positive t-lymphocytes; animal cell; mouse; animals; mice; cancer immunotherapy; melanoma; apoptosis; animal experiment; cyclophosphamide; antineoplastic activity; tumor antigen; monoclonal antibody; cancer inhibition; regulatory t lymphocyte; immunotherapy; drug therapy, combination; t-lymphocytes, regulatory; immunogenicity; tumor cell; melanoma, experimental; single drug dose; adoptive transfer; tumor immunity; effector cell; lymphocytic infiltration; cell expansion; cd134 antigen; immunoglobulin g antibody; monoclonal antibody ox86; drug binding; t lymphocyte activation; lymphocyte depletion; receptors, ox40
Journal Title: Journal of Experimental Medicine
Volume: 206
Issue: 5
ISSN: 0022-1007
Publisher: Rockefeller University Press  
Date Published: 2009-05-11
Start Page: 1103
End Page: 1116
Language: English
DOI: 10.1084/jem.20082205
PUBMED: 19414558
PROVIDER: scopus
PMCID: PMC2715041
Notes: --- - "Cited By (since 1996): 16" - "Export Date: 30 November 2010" - "CODEN: JEMEA" - "Source: Scopus"
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MSK Authors
  1. Jedd D Wolchok
    669 Wolchok
  2. Taha Merghoub
    209 Merghoub
  3. Adam D Cohen
    42 Cohen
  4. Alan N Houghton
    273 Houghton
  5. Alexander Meyer Lesokhin
    118 Lesokhin
  6. Gabrielle A Rizzuto
    21 Rizzuto