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

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.

Pubmed ID: 25539810 RIS Download

Mesh terms: Antibodies, Monoclonal | Antigens, Surface | Antineoplastic Combined Chemotherapy Protocols | CTLA-4 Antigen | Cytokines | Gene Expression Profiling | Gene Expression Regulation, Neoplastic | Humans | Immunophenotyping | Lymphocytes, Tumor-Infiltrating | Neoplasms | Programmed Cell Death 1 Receptor | Signal Transduction | T-Lymphocyte Subsets

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Associated grants

  • Agency: NCI NIH HHS, Id: CA135110
  • Agency: NCI NIH HHS, Id: CA106802
  • Agency: NIAID NIH HHS, Id: R01-AI0792222
  • Agency: NCI NIH HHS, Id: P50-CA121974
  • Agency: NCI NIH HHS, Id: P30 CA008748
  • Agency: NCI NIH HHS, Id: R01 CA106802
  • Agency: NIAID NIH HHS, Id: R01 AI079222
  • Agency: NCI NIH HHS, Id: K24 CA172123
  • Agency: NCATS NIH HHS, Id: UL1 TR000142
  • Agency: NCI NIH HHS, Id: R01 CA135110
  • Agency: NCI NIH HHS, Id: P50 CA121974
  • Agency: NCI NIH HHS, Id: K24CA172123

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