Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo Journal Article
| Authors: | Das, R.; Verma, R.; Sznol, M.; Boddupalli, C. S.; Gettinger, S. N.; Kluger, H.; Callahan, M.; Wolchok, J. D.; Halaban, R.; Dhodapkar, M. V.; Dhodapkar, K. M. |
| Article Title: | Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo |
| 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 Tcell activation, the invivo effects of these drugs in humans remainto 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 invivo 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-1a. 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. |
| Keywords: | clinical article; human tissue; human cell; cancer combination chemotherapy; t lymphocyte; ipilimumab; cancer immunotherapy; gene expression; genetic transcription; in vivo study; immune response; tumor cell; alternative rna splicing; natural killer cell; cytolysis; immunomodulation; monocyte; untranslated rna; cytotoxic t lymphocyte antigen 4; gamma interferon inducible protein 10; interleukin 1alpha; programmed death 1 receptor; memory t lymphocyte; receptor occupancy; nivolumab; human; article; soluble interleukin 2 receptor |
| Journal Title: | Journal of Immunology |
| Volume: | 194 |
| Issue: | 3 |
| ISSN: | 0022-1767 |
| Publisher: | The American Association of Immunologists, Inc |
| Date Published: | 2015-02-01 |
| Start Page: | 950 |
| End Page: | 959 |
| Language: | English |
| DOI: | 10.4049/jimmunol.1401686 |
| PROVIDER: | scopus |
| PUBMED: | 25539810 |
| PMCID: | PMC4380504 |
| DOI/URL: | |
| Notes: | Export Date: 2 March 2015 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work