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

R Das, R Verma, M Sznol, CS Boddupalli… - The Journal of …, 2015 - journals.aai.org
R Das, R Verma, M Sznol, CS Boddupalli, SN Gettinger, H Kluger, M Callahan, JD Wolchok…
The Journal of Immunology, 2015journals.aai.org
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 …
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.
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