title: PD-1 blockade in rhesus macaques: impact on chronic infection and prophylactic vaccination.
abstract: Programmed Cell Death 1 (PD-1) plays a crucial role in immunomodulation. Binding of PD-1 to its ligand receptors down-regulates immune responses, and published reports suggest that this immune modulation is exploited in cases of tumor progression or chronic viral infection to evade immune surveillance. Thus, blockade of this signal could restore or enhance host immune functions. To test this hypothesis, we generated a panel of mAbs specific to human PD-1 that block PD ligand 1 and tested them for in vitro binding, blocking, and functional T cell responses, and evaluated a lead candidate in two in vivo rhesus macaque (Macaca mulatta) models. In the first therapeutic model, chronically SIV-infected macaques were treated with a single infusion of anti-PD-1 mAb; viral loads increased transiently before returning to, or falling below, pretreatment baselines. In the second prophylactic model, naive macaques were immunized with an SIV-gag adenovirus vector vaccine. Induced PD-1 blockade caused a statistically significant (p<0.05) increase in the peak percentage of T cells specific for the CM9 Gag epitope. These new results on PD-1 blockade in nonhuman primates point to a broader role for PD-1 immunomodulation and to potential applications in humans.
authors.affiliation: Vaccine Basic Research, Merck Research Laboratories, West Point, PA 19486, USA. adam_finnefrock@merck.com
authors.forename: Adam C
authors.initials: AC
authors.lastname: Finnefrock
authors.forename: Aimin
authors.initials: A
authors.lastname: Tang
authors.forename: Fengsheng
authors.initials: F
authors.lastname: Li
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Freed
authors.forename: Meizhen
authors.initials: M
authors.lastname: Feng
authors.forename: Kara S
authors.initials: KS
authors.lastname: Cox
authors.forename: Kara J
authors.initials: KJ
authors.lastname: Sykes
authors.forename: James P
authors.initials: JP
authors.lastname: Guare
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: John W
authors.initials: JW
authors.lastname: Shiver
authors.forename: Danilo R
authors.initials: DR
authors.lastname: Casimiro
authors.forename: Tong-Ming
authors.initials: TM
authors.lastname: Fu
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000378:metabolism / Q000502:physiology; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000502:physiology; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism; D060890:B7-H1 Antigen; D002460:Cell Line; D002908:Chronic Disease; D006801:Humans; D007074:Immunoglobulin G / Q000502:physiology; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D061026:Programmed Cell Death 1 Receptor; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000517:prevention & control* / Q000821:virology; D019562:Viral Load
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D007074:Immunoglobulin G; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D018449:SAIDS Vaccines