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Nature. 2017 May 4;545(7652):60-65. doi: 10.1038/nature22079. Epub 2017 Apr 10.

T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.

Author information

1
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
2
Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
3
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
4
Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, Pennsylvania, USA.
5
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
6
Weill Cornell Medical College, New York, New York, USA.
7
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
8
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
9
Immune Monitoring Facility, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
10
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
11
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.
12
Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, New York, USA.
13
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
14
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
15
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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 (Tex cells). 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 Tex cells 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.

PMID:
28397821
PMCID:
PMC5554367
DOI:
10.1038/nature22079
[Indexed for MEDLINE]
Free PMC Article

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