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J Immunol. 2015 Feb 1;194(3):950-9. doi: 10.4049/jimmunol.1401686. Epub 2014 Dec 24.

Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo.

Author information

  • 1Department of Medicine, Yale University School of Medicine, New Haven, CT 06520; Smilow Cancer Center, Yale University School of Medicine, New Haven, CT 06520;
  • 2Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
  • 3Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520; and.
  • 4Department of Medicine, Yale University School of Medicine, New Haven, CT 06520; Smilow Cancer Center, Yale University School of Medicine, New Haven, CT 06520; Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520 kavita.dhodapkar@yale.edu.

Abstract

Combination therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor effects. Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. To better understand biologic effects of therapy, we analyzed blood/tumor tissue from 45 patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinct genomic and functional signatures in vivo in purified human T cells and monocytes. Therapy-induced changes are more prominent in T cells than in monocytes and involve largely nonoverlapping changes in coding genes, including alternatively spliced transcripts and noncoding RNAs. Pathway analysis revealed that CTLA-4 blockade induces a proliferative signature predominantly in a subset of transitional memory T cells, whereas PD-1 blockade instead leads to changes in genes implicated in cytolysis and NK cell function. Combination blockade leads to nonoverlapping changes in gene expression, including proliferation-associated and chemokine genes. These therapies also have differential effects on plasma levels of CXCL10, soluble IL-2R, and IL-1α. Importantly, PD-1 receptor occupancy following anti-PD-1 therapy may be incomplete in the tumor T cells even in the setting of complete receptor occupancy in circulating T cells. These data demonstrate that, despite shared property of checkpoint blockade, Abs against PD-1, CTLA-4 alone, or in combination have distinct immunologic effects in vivo. Improved understanding of pharmacodynamic effects of these agents in patients will support rational development of immune-based combinations against cancer.

PMID:
25539810
PMCID:
PMC4380504
DOI:
10.4049/jimmunol.1401686
[PubMed - indexed for MEDLINE]
Free PMC Article
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