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 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.
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06520; Smilow Cancer Center, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Rituparna
authors.initials: R
authors.lastname: Das
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06520; Smilow Cancer Center, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Rakesh
authors.initials: R
authors.lastname: Verma
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06520; Smilow Cancer Center, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06520; Smilow Cancer Center, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Boddupalli
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06520; Smilow Cancer Center, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Scott N
authors.initials: SN
authors.lastname: Gettinger
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06520; Smilow Cancer Center, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Harriet
authors.initials: H
authors.lastname: Kluger
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
authors.forename: Margaret
authors.initials: M
authors.lastname: Callahan
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520; and.
authors.forename: Ruth
authors.initials: R
authors.lastname: Halaban
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06520; Smilow Cancer Center, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Madhav V
authors.initials: MV
authors.lastname: Dhodapkar
authors.affiliation: Department 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.
authors.forename: Kavita M
authors.initials: KM
authors.lastname: Dhodapkar
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D000954:Antigens, Surface; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D016207:Cytokines / Q000097:blood; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D000074324:Ipilimumab; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D060908:CTLA-4 Antigen; D016207:Cytokines; D000074324:Ipilimumab; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab