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

Alexander C. Huang (), Michael A. Postow, Robert J. Orlowski, Rosemarie Mick, Bertram Bengsch, Sasikanth Manne, Wei Xu, Shannon Harmon, Josephine R. Giles, Brandon Wenz, Matthew Adamow, Deborah Kuk, Katherine S. Panageas, Cristina Carrera, Phillip Wong, Felix Quagliarello, Bradley Wubbenhorst, Kurt D’Andrea, Kristen E. Pauken, Ramin S. Herati, Ryan P. Staupe, Jason M. Schenkel, Suzanne McGettigan, Shawn Kothari, Sangeeth M. George, Robert H. Vonderheide, Ravi K. Amaravadi, Giorgos C. Karakousis, Lynn M. Schuchter, Xiaowei Xu, Katherine L. Nathanson, Jedd D. Wolchok, Tara C. Gangadhar () and E. John Wherry ()
Additional contact information
Alexander C. Huang: Perelman School of Medicine, University of Pennsylvania
Michael A. Postow: Memorial Sloan Kettering Cancer Center
Robert J. Orlowski: Perelman School of Medicine, University of Pennsylvania
Rosemarie Mick: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania
Bertram Bengsch: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Sasikanth Manne: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Wei Xu: Perelman School of Medicine, University of Pennsylvania
Shannon Harmon: Perelman School of Medicine, University of Pennsylvania
Josephine R. Giles: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Brandon Wenz: Perelman School of Medicine, University of Pennsylvania
Matthew Adamow: Immune Monitoring Facility, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center
Deborah Kuk: Memorial Sloan Kettering Cancer Center
Katherine S. Panageas: Memorial Sloan Kettering Cancer Center
Cristina Carrera: Memorial Sloan Kettering Cancer Center
Phillip Wong: Immune Monitoring Facility, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center
Felix Quagliarello: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Bradley Wubbenhorst: Perelman School of Medicine, University of Pennsylvania
Kurt D’Andrea: Perelman School of Medicine, University of Pennsylvania
Kristen E. Pauken: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Ramin S. Herati: Perelman School of Medicine, University of Pennsylvania
Ryan P. Staupe: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Jason M. Schenkel: Brigham and Women’s Hospital
Suzanne McGettigan: Perelman School of Medicine, University of Pennsylvania
Shawn Kothari: Perelman School of Medicine, University of Pennsylvania
Sangeeth M. George: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Robert H. Vonderheide: Perelman School of Medicine, University of Pennsylvania
Ravi K. Amaravadi: Perelman School of Medicine, University of Pennsylvania
Giorgos C. Karakousis: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania
Lynn M. Schuchter: Perelman School of Medicine, University of Pennsylvania
Xiaowei Xu: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania
Katherine L. Nathanson: Perelman School of Medicine, University of Pennsylvania
Jedd D. Wolchok: Memorial Sloan Kettering Cancer Center
Tara C. Gangadhar: Perelman School of Medicine, University of Pennsylvania
E. John Wherry: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania

Nature, 2017, vol. 545, issue 7652, 60-65

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature22079

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