Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy

被引：235

作者：

Johanns, Tanner M. ^{[1
,2
]}

Miller, Christopher A. ^{[3
,4
]}

Dorward, Ian G. ^{[5
]}

Tsien, Christina ^{[6
]}

Chang, Edward ^{[7
]}

Perry, Arie ^{[7
,8
]}

Uppaluri, Ravindra ^{[9
]}

Ferguson, Cole ^{[10
]}

Schmidt, Robert E. ^{[10
]}

Dahiya, Sonika ^{[10
]}

Ansstas, George ^{[1
,2
,11
,12
]}

Mardis, Elaine R. ^{[3
,4
,11
,12
]}

Dunn, Gavin P. ^{[2
,5
,11
,12
]}

机构：

[1] Washington Univ, Sch Med, Dept Med, Div Oncol, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Ctr Human Immunol & Immunotherapy Programs, 660 South Euclid Ave,Box 8057, St Louis, MO 63110 USA

[3] Washington Univ, McDonnell Genome Inst, St Louis, MO USA

[4] Washington Univ, Sch Med, Dept Med, Div Genom & Bioinformat, St Louis, MO 63110 USA

[5] Washington Univ, Sch Med, Dept Neurol Surg, 660 South Euclid Ave,Box 8057, St Louis, MO 63110 USA

[6] Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO USA

[7] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA

[8] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA

[9] Washington Univ, Sch Med, Dept Otolaryngol, St Louis, MO 63110 USA

[10] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA

[11] Barnes Jewish Hosp, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA

[12] Washington Univ, Sch Med, St Louis, MO USA

来源：

CANCER DISCOVERY | 2016年 / 6卷 / 11期

关键词：

COLORECTAL ADENOMAS; ANALYSIS REVEALS; WHOLE-GENOME; MUTATIONS; EVOLUTION; TEMOZOLOMIDE; NEOANTIGENS; SENSITIVITY; PROGRESSION; ELICIT;

D O I：

10.1158/2159-8290.CD-16-0575

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

We present the case of a patient with a left frontal glioblastoma with primitive neuroectodermal tumor features and hypermutated genotype in the setting of a POLE germline alteration. During standard-of-care chemoradiation, the patient developed a cervical spine metastasis and was subsequently treated with pembrolizumab. Shortly thereafter, the patient developed an additional metastatic spinal lesion. Using whole-exome DNA sequencing and clonal analysis, we report changes in the subclonal architecture throughout treatment. Furthermore, a persistently high neoantigen load was observed within all tumors. Interestingly, following initiation of pembrolizumab, brisk lymphocyte infiltration was observed in the subsequently resected metastatic spinal lesion and an objective radiographic response was noted in a progressive intracranial lesion, suggestive of active central nervous system (CNS) immunosurveillance following checkpoint blockade therapy. SIGNIFICANCE: It is unclear whether hypermutated glioblastomas are susceptible to checkpoint blockade in adults. Herein, we provide proof of principle that glioblastomas with DNA-repair defects treated with checkpoint blockade may result in CNS immune activation, leading to clinically and immunologically significant responses. These patients may represent a genomically stratified group for whom immunotherapy could be considered. (C)2016 AACR.

引用

页码：1230 / 1236

页数：7

共 32 条

[1]

Adzhubei Ivan, 2013, Curr Protoc Hum Genet, VChapter 7, DOI 10.1002/0471142905.hg0720s76

[2] Signatures of mutational processes in human cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Aparicio, Samuel A. J. R. ;

Behjati, Sam ;

Biankin, Andrew V. ;

Bignell, Graham R. ;

Bolli, Niccolo ;

Borg, Ake ;

Borresen-Dale, Anne-Lise ;

Boyault, Sandrine ;

Burkhardt, Birgit ;

Butler, Adam P. ;

Caldas, Carlos ;

Davies, Helen R. ;

Desmedt, Christine ;

Eils, Roland ;

Eyfjord, Jorunn Erla ;

Foekens, John A. ;

Greaves, Mel ;

Hosoda, Fumie ;

Hutter, Barbara ;

Ilicic, Tomislav ;

Imbeaud, Sandrine ;

Imielinsk, Marcin ;

Jaeger, Natalie ;

Jones, David T. W. ;

Jones, David ;

Knappskog, Stian ;

Kool, Marcel ;

Lakhani, Sunil R. ;

Lopez-Otin, Carlos ;

Martin, Sancha ;

Munshi, Nikhil C. ;

Nakamura, Hiromi ;

Northcott, Paul A. ;

Pajic, Marina ;

Papaemmanuil, Elli ;

Paradiso, Angelo ;

Pearson, John V. ;

Puente, Xose S. ;

Raine, Keiran ;

Ramakrishna, Manasa ;

Richardson, Andrea L. ;

Richter, Julia ;

Rosenstiel, Philip ;

Schlesner, Matthias ;

Schumacher, Ton N. ;

Span, Paul N. ;

Teague, Jon W. .

NATURE, 2013, 500 (7463) :415-+

[3] Molecular and cellular heterogeneity: the hallmark of glioblastoma [J].

Aum, Diane J. ;

Kim, David H. ;

Beaumont, Thomas L. ;

Leuthardt, Eric C. ;

Dunn, Gavin P. ;

Kim, Albert H. .

NEUROSURGICAL FOCUS, 2014, 37 (06)

[4] Comprehensive molecular characterization of gastric adenocarcinoma [J].

Bass, Adam J. ;

Thorsson, Vesteinn ;

Shmulevich, Ilya ;

Reynolds, Sheila M. ;

Miller, Michael ;

Bernard, Brady ;

Hinoue, Toshinori ;

Laird, Peter W. ;

Curtis, Christina ;

Shen, Hui ;

Weisenberger, Daniel J. ;

Schultz, Nikolaus ;

Shen, Ronglai ;

Weinhold, Nils ;

Keiser, David P. ;

Bowlby, Reanne ;

Sipahimalani, Payal ;

Cherniack, Andrew D. ;

Getz, Gad ;

Liu, Yingchun ;

Noble, Michael S. ;

Pedamallu, Chandra ;

Sougnez, Carrie ;

Taylor-Weiner, Amaro ;

Akbani, Rehan ;

Lee, Ju-Seog ;

Liu, Wenbin ;

Mills, Gordon B. ;

Yang, Da ;

Zhang, Wei ;

Pantazi, Angeliki ;

Parfenov, Michael ;

Gulley, Margaret ;

Piazuelo, M. Blanca ;

Schneider, Barbara G. ;

Kim, Jihun ;

Boussioutas, Alex ;

Sheth, Margi ;

Demchok, John A. ;

Rabkin, Charles S. ;

Willis, Joseph E. ;

Ng, Sam ;

Garman, Katherine ;

Beer, David G. ;

Pennathur, Arjun ;

Raphael, Benjamin J. ;

Wu, Hsin-Ta ;

Odze, Robert ;

Kim, Hark K. ;

Bowen, Jay .

NATURE, 2014, 513 (7517) :202-209

[5] Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency [J].

Bouffet, Eric ;

Larouche, Valerie ;

Campbell, Brittany B. ;

Merico, Daniele ;

de Borja, Richard ;

Aronson, Melyssa ;

Durno, Carol ;

Krueger, Joerg ;

Cabric, Vanja ;

Ramaswamy, Vijay ;

Zhukova, Nataliya ;

Mason, Gary ;

Farah, Roula ;

Afzal, Samina ;

Yalon, Michal ;

Rechavi, Gideon ;

Magimairajan, Vanan ;

Walsh, Michael F. ;

Constantini, Shlomi ;

Dvir, Rina ;

Elhasid, Ronit ;

Reddy, Alyssa ;

Osborn, Michael ;

Sullivan, Michael ;

Hansford, Jordan ;

Dodgshun, Andrew ;

Klauber-Demore, Nancy ;

Peterson, Lindsay ;

Patel, Sunil ;

Lindhorst, Scott ;

Atkinson, Jeffrey ;

Cohen, Zane ;

Laframboise, Rachel ;

Dirks, Peter ;

Taylor, Michael ;

Malkin, David ;

Albrecht, Steffen ;

Dudley, Roy W. R. ;

Jabado, Nada ;

Hawkins, Cynthia E. ;

Shlien, Adam ;

Tabori, Uri .

JOURNAL OF CLINICAL ONCOLOGY, 2016, 34 (19) :2206-+

[6] Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment [J].

Cahill, Daniel P. ;

Levine, Kymberly K. ;

Betensky, Rebecca A. ;

Codd, Patrick J. ;

Romany, Candice A. ;

Reavie, Linsey B. ;

Batchelor, Tracy T. ;

Futreal, P. Andrew ;

Stratton, Michael R. ;

Curry, William T. ;

Iafrate, A. John ;

Louis, David N. .

CLINICAL CANCER RESEARCH, 2007, 13 (07) :2038-2045

[7] Comprehensive genomic characterization defines human glioblastoma genes and core pathways [J].

Chin, L. ;

Meyerson, M. ;

Aldape, K. ;

Bigner, D. ;

Mikkelsen, T. ;

VandenBerg, S. ;

Kahn, A. ;

Penny, R. ;

Ferguson, M. L. ;

Gerhard, D. S. ;

Getz, G. ;

Brennan, C. ;

Taylor, B. S. ;

Winckler, W. ;

Park, P. ;

Ladanyi, M. ;

Hoadley, K. A. ;

Verhaak, R. G. W. ;

Hayes, D. N. ;

Spellman, Paul T. ;

Absher, D. ;

Weir, B. A. ;

Ding, L. ;

Wheeler, D. ;

Lawrence, M. S. ;

Cibulskis, K. ;

Mardis, E. ;

Zhang, Jinghui ;

Wilson, R. K. ;

Donehower, L. ;

Wheeler, D. A. ;

Purdom, E. ;

Wallis, J. ;

Laird, P. W. ;

Herman, J. G. ;

Schuebel, K. E. ;

Weisenberger, D. J. ;

Baylin, S. B. ;

Schultz, N. ;

Yao, Jun ;

Wiedemeyer, R. ;

Weinstein, J. ;

Sander, C. ;

Gibbs, R. A. ;

Gray, J. ;

Kucherlapati, R. ;

Lander, E. S. ;

Myers, R. M. ;

Perou, C. M. ;

McLendon, Roger .

NATURE, 2008, 455 (7216) :1061-1068

[8] Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing [J].

Ding, Li ;

Ley, Timothy J. ;

Larson, David E. ;

Miller, Christopher A. ;

Koboldt, Daniel C. ;

Welch, John S. ;

Ritchey, Julie K. ;

Young, Margaret A. ;

Lamprecht, Tamara ;

McLellan, Michael D. ;

McMichael, Joshua F. ;

Wallis, John W. ;

Lu, Charles ;

Shen, Dong ;

Harris, Christopher C. ;

Dooling, David J. ;

Fulton, Robert S. ;

Fulton, Lucinda L. ;

Chen, Ken ;

Schmidt, Heather ;

Kalicki-Veizer, Joelle ;

Magrini, Vincent J. ;

Cook, Lisa ;

McGrath, Sean D. ;

Vickery, Tammi L. ;

Wendl, Michael C. ;

Heath, Sharon ;

Watson, Mark A. ;

Link, Daniel C. ;

Tomasson, Michael H. ;

Shannon, William D. ;

Payton, Jacqueline E. ;

Kulkarni, Shashikant ;

Westervelt, Peter ;

Walter, Matthew J. ;

Graubert, Timothy A. ;

Mardis, Elaine R. ;

Wilson, Richard K. ;

DiPersio, John F. .

NATURE, 2012, 481 (7382) :506-510

[9] Principles of immunology and its nuances in the central nervous system [J].

Dunn, Gavin P. ;

Okada, Hideho .

NEURO-ONCOLOGY, 2015, 17 :3-8

[10] Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis [J].

Erson-Omay, E. Zeynep ;

Caglayan, Ahmet Okay ;

Schultz, Nikolaus ;

Weinhold, Nils ;

Omay, S. Bulent ;

Ozduman, Koray ;

Koksal, Yavuz ;

Li, Jie ;

Harmanci, Akdes Serin ;

Clark, Victoria ;

Carrion-Grant, Geneive ;

Baranoski, Jacob ;

Caglar, Caner ;

Barak, Tanyeri ;

Coskun, Suleyman ;

Baran, Burcin ;

Kose, Dogan ;

Sun, Jia ;

Bakircioglu, Mehmet ;

Gunel, Jennifer Moliterno ;

Pamir, M. Necmettin ;

Mishra-Gorur, Ketu ;

Bilguvar, Kaya ;

Yasuno, Katsuhito ;

Vortmeyer, Alexander ;

Huttner, Anita J. ;

Sander, Chris ;

Gunel, Murat .

NEURO-ONCOLOGY, 2015, 17 (10) :1356-1364

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