title: T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.
abstract: Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Texcells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Texcells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Huang
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Weill Cornell Medical College, New York, New York, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Postow
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Orlowski
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Mick
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Bertram
authors.initials: B
authors.lastname: Bengsch
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Sasikanth
authors.initials: S
authors.lastname: Manne
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Harmon
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Josephine R
authors.initials: JR
authors.lastname: Giles
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Wenz
authors.affiliation: Immune Monitoring Facility, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Adamow
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Kuk
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Panageas
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Dermatology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Carrera
authors.affiliation: Immune Monitoring Facility, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Wong
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Quagliarello
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Wubbenhorst
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: D'Andrea
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Pauken
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ramin S
authors.initials: RS
authors.lastname: Herati
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Staupe
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Schenkel
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: McGettigan
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Kothari
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Sangeeth M
authors.initials: SM
authors.lastname: George
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Giorgos C
authors.initials: GC
authors.lastname: Karakousis
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schuchter
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Tara C
authors.initials: TC
authors.lastname: Gangadhar
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000276:immunology / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D009367:Neoplasm Staging; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000276:immunology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019394:Ki-67 Antigen; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab