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Cancer Immunology Research
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Clinical Trials of Cancer Immunotherapies

Abstract PR05: Peripheral blood immune profiling of anti-PD-1 therapy in human melanoma reveals a link between T cell re-invigoration and tumor burden that predicts response

Alexander Huang, Michael A. Postow, Robert J. Orlowski, Rosemarie Mick, Bertram Bengsch, Sasi Manne, Wei Xu, Shannon Harmon, Matthew Adamow, Deborah Kuk, Katherine Panangeas, Cristina Carerra, Phillip Wong, Felix Quagliarello, Kristen E. Pauken, Ramin S. Herati, Suzanne McGettigan, Shawn Kothari, Sangeeth M. George, Brandon Wenz, Kurt D'Andrea, Xiaowei Xu, Ravi K. Amaravadi, Giorgos Karakousis, Lynn M. Schuchter, Katherine L. Nathanson, Jedd D. Wolchok, Tara C. Gangadhar and John Wherry
Alexander Huang
1University of Pennsylvania, Philadelphia, PA;
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Michael A. Postow
2Memorial Sloan Kettering Cancer Center, New York City, NY.
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Robert J. Orlowski
1University of Pennsylvania, Philadelphia, PA;
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Rosemarie Mick
1University of Pennsylvania, Philadelphia, PA;
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Bertram Bengsch
1University of Pennsylvania, Philadelphia, PA;
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Sasi Manne
1University of Pennsylvania, Philadelphia, PA;
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Wei Xu
1University of Pennsylvania, Philadelphia, PA;
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Shannon Harmon
1University of Pennsylvania, Philadelphia, PA;
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Matthew Adamow
2Memorial Sloan Kettering Cancer Center, New York City, NY.
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Deborah Kuk
2Memorial Sloan Kettering Cancer Center, New York City, NY.
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Katherine Panangeas
2Memorial Sloan Kettering Cancer Center, New York City, NY.
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Cristina Carerra
2Memorial Sloan Kettering Cancer Center, New York City, NY.
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Phillip Wong
2Memorial Sloan Kettering Cancer Center, New York City, NY.
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Felix Quagliarello
1University of Pennsylvania, Philadelphia, PA;
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Kristen E. Pauken
1University of Pennsylvania, Philadelphia, PA;
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Ramin S. Herati
1University of Pennsylvania, Philadelphia, PA;
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Suzanne McGettigan
1University of Pennsylvania, Philadelphia, PA;
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Shawn Kothari
1University of Pennsylvania, Philadelphia, PA;
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Sangeeth M. George
1University of Pennsylvania, Philadelphia, PA;
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Brandon Wenz
1University of Pennsylvania, Philadelphia, PA;
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Kurt D'Andrea
1University of Pennsylvania, Philadelphia, PA;
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Xiaowei Xu
1University of Pennsylvania, Philadelphia, PA;
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Ravi K. Amaravadi
1University of Pennsylvania, Philadelphia, PA;
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Giorgos Karakousis
1University of Pennsylvania, Philadelphia, PA;
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Lynn M. Schuchter
1University of Pennsylvania, Philadelphia, PA;
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Katherine L. Nathanson
1University of Pennsylvania, Philadelphia, PA;
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Jedd D. Wolchok
2Memorial Sloan Kettering Cancer Center, New York City, NY.
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Tara C. Gangadhar
1University of Pennsylvania, Philadelphia, PA;
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John Wherry
1University of Pennsylvania, Philadelphia, PA;
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DOI: 10.1158/2326-6066.IMM2016-PR05 Published November 2016
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Abstracts: Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; September 25-28, 2016; New York, NY

Abstract

Despite the clinical success of PD-1 based therapies in human melanoma patients, the majority of patients do not have durable clinical benefit from anti-PD-1 monotherapy. A major challenge remains identifying which patients will respond to anti-PD-1 therapy and defining the underlying reasons for successful response versus treatment failure. Pre-existing T cell infiltration and/or PD-L1 expression in tumors may predict clinical responses; however, the use of blood-based profiling to understand the immunologic mechanism of PD-1 blockade has been less explored. Here we used detailed immune profiling of peripheral blood from stage IV melanoma patients before and after pembrolizumab (pembro), and identified pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (TEX). Robust induction of Ki67 in this subset of circulating CD8 T cells post-therapy (re-invigoration) occurred in 78% of patients indicating strong, on target immunological effects of PD-1 blockade in most patients studied here. Despite this high immunological response rate, the objective clinical response rate in this cohort was less than 40%. Ki67 in CD8 T cells alone did not predict clinical outcomes and, in fact, higher systemic immune activation at baseline was associated with lower overall survival. Rather, the magnitude of re-invigoration of circulating TEX in relation to pre-treatment tumor burden correlated with clinical response. We identified a TEX re-invigoration to tumor burden ratio which could be used to predict clinical response and overall survival as early as 6 weeks post therapy. Consistent observations were found in a second independent cohort and suggest that clinical failure of PD-1 blockade in many patients may not solely be due to an inability to induce immune re-invigoration but rather, an imbalance between T cell re-invigoration and tumor burden. Thus, by focused profiling of a mechanistically relevant circulating T cell subpopulation calibrated to pre-treatment disease burden, we identify a clinically accessible predictor of response to PD-1 blockade. These findings also provide a framework for dissecting distinct types of treatment failures in melanoma and have implications for stratifying patients into additional immunotherapeutic treatment approaches.

Citation Format: Alexander Huang, Michael A. Postow, Robert J. Orlowski, Rosemarie Mick, Bertram Bengsch, Sasi Manne, Wei Xu, Shannon Harmon, Matthew Adamow, Deborah Kuk, Katherine Panangeas, Cristina Carerra, Phillip Wong, Felix Quagliarello, Kristen E. Pauken, Ramin S. Herati, Suzanne McGettigan, Shawn Kothari, Sangeeth M. George, Brandon Wenz, Kurt D'Andrea, Xiaowei Xu, Ravi K. Amaravadi, Giorgos Karakousis, Lynn M. Schuchter, Katherine L. Nathanson, Jedd D. Wolchok, Tara C. Gangadhar, John Wherry. Peripheral blood immune profiling of anti-PD-1 therapy in human melanoma reveals a link between T cell re-invigoration and tumor burden that predicts response [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr PR05.

  • ©2016 American Association for Cancer Research.
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Cancer Immunology Research: 4 (11 Supplement)
November 2016
Volume 4, Issue 11 Supplement
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Abstract PR05: Peripheral blood immune profiling of anti-PD-1 therapy in human melanoma reveals a link between T cell re-invigoration and tumor burden that predicts response
Alexander Huang, Michael A. Postow, Robert J. Orlowski, Rosemarie Mick, Bertram Bengsch, Sasi Manne, Wei Xu, Shannon Harmon, Matthew Adamow, Deborah Kuk, Katherine Panangeas, Cristina Carerra, Phillip Wong, Felix Quagliarello, Kristen E. Pauken, Ramin S. Herati, Suzanne McGettigan, Shawn Kothari, Sangeeth M. George, Brandon Wenz, Kurt D'Andrea, Xiaowei Xu, Ravi K. Amaravadi, Giorgos Karakousis, Lynn M. Schuchter, Katherine L. Nathanson, Jedd D. Wolchok, Tara C. Gangadhar and John Wherry
Cancer Immunol Res November 1 2016 (4) (11 Supplement) PR05; DOI: 10.1158/2326-6066.IMM2016-PR05

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Abstract PR05: Peripheral blood immune profiling of anti-PD-1 therapy in human melanoma reveals a link between T cell re-invigoration and tumor burden that predicts response
Alexander Huang, Michael A. Postow, Robert J. Orlowski, Rosemarie Mick, Bertram Bengsch, Sasi Manne, Wei Xu, Shannon Harmon, Matthew Adamow, Deborah Kuk, Katherine Panangeas, Cristina Carerra, Phillip Wong, Felix Quagliarello, Kristen E. Pauken, Ramin S. Herati, Suzanne McGettigan, Shawn Kothari, Sangeeth M. George, Brandon Wenz, Kurt D'Andrea, Xiaowei Xu, Ravi K. Amaravadi, Giorgos Karakousis, Lynn M. Schuchter, Katherine L. Nathanson, Jedd D. Wolchok, Tara C. Gangadhar and John Wherry
Cancer Immunol Res November 1 2016 (4) (11 Supplement) PR05; DOI: 10.1158/2326-6066.IMM2016-PR05
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