Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo
2015
Combination therapy concurrently targeting PD-1 and
CTLA-4
immune checkpointsleads to remarkable antitumor effects. Although both PD-1 and
CTLA-4dampen 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
blockadeof
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 analysisrevealed that
CTLA-4
blockadeinduces a proliferative signature predominantly in a subset of transitional
memory T cells, whereas PD-1
blockadeinstead leads to changes in genes implicated in
cytolysisand NK cell function. Combination
blockadeleads 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-4alone, 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.
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