Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency

被引：655

作者：

Bouffet, Eric ^{[1
]}

Larouche, Valerie ^{[3
]}

Campbell, Brittany B. ^{[1
]}

Merico, Daniele ^{[1
]}

de Borja, Richard ^{[1
]}

Aronson, Melyssa ^{[2
]}

Durno, Carol ^{[1
]}

Krueger, Joerg ^{[1
]}

Cabric, Vanja ^{[1
]}

Ramaswamy, Vijay ^{[1
]}

Zhukova, Nataliya ^{[1
]}

Mason, Gary ^{[9
]}

Farah, Roula ^{[10
]}

Afzal, Samina ^{[6
]}

Yalon, Michal ^{[11
]}

Rechavi, Gideon ^{[11
]}

Magimairajan, Vanan ^{[7
,8
]}

Walsh, Michael F. ^{[13
]}

Constantini, Shlomi ^{[12
]}

Dvir, Rina ^{[12
]}

Elhasid, Ronit ^{[12
]}

Reddy, Alyssa ^{[14
]}

Osborn, Michael ^{[15
]}

Sullivan, Michael ^{[16
]}

Hansford, Jordan ^{[16
]}

Dodgshun, Andrew ^{[16
]}

Klauber-Demore, Nancy ^{[17
]}

Peterson, Lindsay ^{[17
]}

Patel, Sunil ^{[17
]}

Lindhorst, Scott ^{[17
]}

Atkinson, Jeffrey ^{[4
]}

Cohen, Zane ^{[2
]}

Laframboise, Rachel ^{[3
]}

Dirks, Peter ^{[1
]}

Taylor, Michael ^{[1
]}

Malkin, David ^{[1
]}

Albrecht, Steffen ^{[5
]}

Dudley, Roy W. R. ^{[5
]}

Jabado, Nada ^{[5
]}

Hawkins, Cynthia E. ^{[1
]}

Shlien, Adam ^{[1
]}

Tabori, Uri ^{[1
]}

机构：

[1] Hosp Sick Children, 555 Univ Ave, Toronto, ON M5G 1X8, Canada

[2] Zane Cohen Ctr Digest Dis, Mt Sinai, ON, Canada

[3] Univ Laval, Quebec City, PQ, Canada

[4] Montreal Childrens Hosp, Montreal, PQ H3H 1P3, Canada

[5] McGill Univ, Montreal, PQ, Canada

[6] IWK Hlth Ctr, Halifax, NS, Canada

[7] Canc Care Manitoba, Winnipeg, MB, Canada

[8] Univ Manitoba, Winnipeg, MB, Canada

[9] Univ Pittsburgh, Childrens Hosp Pittsburgh, Med Ctr, Pittsburgh, PA 15213 USA

[10] St George Hosp Univ, Med Ctr, Beirut, Lebanon

[11] Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel

[12] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel

[13] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[14] Univ Alabama Birmingham, Birmingham, AL USA

[15] Womens & Childrens Hosp, Adelaide, SA, Australia

[16] Royal Childrens Hosp, Melbourne, Vic, Australia

[17] Med Univ S Carolina, Charleston, SC 29425 USA

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2016年 / 34卷 / 19期

关键词：

HIGH-GRADE GLIOMAS; CELL LUNG-CANCER; CHILDRENS ONCOLOGY GROUP; MALIGNANT GLIOMAS; CTLA-4; BLOCKADE; PD-1; MUTATIONS; MELANOMA; IMMUNOTHERAPY; TEMOZOLOMIDE;

D O I：

10.1200/JCO.2016.66.6552

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose Recurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition. Patients and Methods We performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab. Results All malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 +/- standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 +/- standard deviation, 1,043), similar to other cancers that responded favorably to immune checkpoint inhibitors. bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all other brain tumors (P < .001). bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas, lung cancers, or microsatellite-unstable GI cancers (P < .001). On the basis of these preclinical data, we treated two bMMRD siblings with recurrent multifocal GBM with the anti-programmed death-1 inhibitor nivolumab, which resulted in clinically significant responses and a profound radiologic response. Conclusion This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD. (C) 2016 by American Society of Clinical Oncology

引用

页码：2206 / +

页数：9

共 27 条

[1] High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan [J].

Amayiri, Nisreen ;

Tabori, Uri ;

Campbell, Brittany ;

Bakry, Doua ;

Aronson, Melyssa ;

Durno, Carol ;

Rakopoulos, Patricia ;

Malkin, David ;

Qaddoumi, Ibrahim ;

Musharbash, Awni ;

Swaidan, Maisa ;

Bouffet, Eric ;

Hawkins, Cynthia ;

Al-Hussaini, Maysa .

INTERNATIONAL JOURNAL OF CANCER, 2016, 138 (02) :380-385

[2] Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium [J].

Bakry, Doua ;

Aronson, Melyssa ;

Durno, Carol ;

Rimawi, Hala ;

Farah, Roula ;

Alharbi, Qasim Kholaif ;

Alharbi, Musa ;

Shamvil, Ashraf ;

Ben-Shachar, Shay ;

Mistry, Matthew ;

Constantini, Shlomi ;

Dvir, Rina ;

Qaddoumi, Ibrahim ;

Gallinger, Steven ;

Lerner-Ellis, Jordan ;

Pollett, Aaron ;

Stephens, Derek ;

Kelies, Steve ;

Chao, Elizabeth ;

Malkin, David ;

Bouffet, Eric ;

Hawkins, Cynthia ;

Tabori, Uri .

EUROPEAN JOURNAL OF CANCER, 2014, 50 (05) :987-996

[3] Temozolomide in the treatment of high-grade gliomas in children: a report from the Children's Oncology Group [J].

Cohen, Kenneth J. ;

Pollack, Ian F. ;

Zhou, Tianni ;

Buxton, Allen ;

Holmes, Emiko J. ;

Burger, Peter C. ;

Brat, Daniel J. ;

Rosenblum, Marc K. ;

Hamilton, Ronald L. ;

Lavey, Robert S. ;

Heideman, Richard L. .

NEURO-ONCOLOGY, 2011, 13 (03) :317-323

[4] Oncologic surveillance for subjects with biallelic mismatch repair gene mutations: 10 year follow-up of a kindred [J].

Durno, Carol A. ;

Aronson, Melyssa ;

Tabori, Uri ;

Malkin, David ;

Gallinger, Steven ;

Chan, Helen S. L. .

PEDIATRIC BLOOD & CANCER, 2012, 59 (04) :652-656

[5] CheckMate 067-frontline nivolumab improves PFS alone or in combination with ipilimumab [J].

Errico, Alessia .

NATURE REVIEWS CLINICAL ONCOLOGY, 2015, 12 (08) :435-435

[6] RANDOMIZED PHASE-III TRIAL IN CHILDHOOD HIGH-GRADE ASTROCYTOMA COMPARING VINCRISTINE, LOMUSTINE, AND PREDNISONE WITH THE 8-DRUGS-IN-1-DAY REGIMEN [J].

FINLAY, JL ;

BOYETT, JM ;

YATES, AJ ;

WISOFF, JH ;

MILSTEIN, JM ;

GEYER, JR ;

BERTOLONE, SJ ;

MCGUIRE, P ;

CHERLOW, JM ;

TEFFT, M ;

TURSKI, PA ;

WARA, WM ;

EDWARDS, M ;

SUTTON, LN ;

BERGER, MS ;

EPSTEIN, F ;

AYERS, G ;

ALLEN, JC ;

PACKER, RJ .

JOURNAL OF CLINICAL ONCOLOGY, 1995, 13 (01) :112-123

[7] Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer [J].

Garon, Edward B. ;

Rizvi, Naiyer A. ;

Hui, Rina ;

Leighl, Natasha ;

Balmanoukian, Ani S. ;

Eder, Joseph Paul ;

Patnaik, Amita ;

Aggarwal, Charu ;

Gubens, Matthew ;

Horn, Leora ;

Carcereny, Enric ;

Ahn, Myung-Ju ;

Felip, Enriqueta ;

Lee, Jong-Seok ;

Hellmann, Matthew D. ;

Hamid, Omid ;

Goldman, Jonathan W. ;

Soria, Jean-Charles ;

Dolled-Filhart, Marisa ;

Rutledge, Ruth Z. ;

Zhang, Jin ;

Lunceford, Jared K. ;

Rangwala, Reshma ;

Lubiniecki, Gregory M. ;

Roach, Charlotte ;

Emancipator, Kenneth ;

Gandhi, Leena .

NEW ENGLAND JOURNAL OF MEDICINE, 2015, 372 (21) :2018-2028

[8] Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer [J].

Gettinger, Scott N. ;

Horn, Leora ;

Gandhi, Leena ;

Spigel, David R. ;

Antonia, Scott J. ;

Rizvi, Naiyer A. ;

Powderly, John D. ;

Heist, Rebecca S. ;

Carvajal, Richard D. ;

Jackman, David M. ;

Sequist, Lecia V. ;

Smith, David C. ;

Leming, Philip ;

Carbone, David P. ;

Pinder-Schenck, Mary C. ;

Topalian, Suzanne L. ;

Hodi, F. Stephen ;

Sosman, Jeffrey A. ;

Sznol, Mario ;

McDermott, David F. ;

Pardoll, Drew M. ;

Sankar, Vindira ;

Ahlers, Christoph M. ;

Salvati, Mark ;

Wigginton, Jon M. ;

Hellmann, Matthew D. ;

Kollia, Georgia D. ;

Gupta, Ashok K. ;

Brahmer, Julie R. .

JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (18) :2004-U32

[9] The odds of immunotherapy success [J].

Gubin, Matthew M. ;

Schreiber, Robert D. .

SCIENCE, 2015, 350 (6257) :158-159

[10] A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy [J].

Hunter, C ;

Smith, R ;

Cahill, DP ;

Stephens, P ;

Stevens, C ;

Teague, J ;

Greenman, C ;

Edkins, S ;

Bignell, G ;

Davies, H ;

O'Meara, S ;

Parker, A ;

Avis, T ;

Barthorpe, S ;

Brackenbury, L ;

Buck, G ;

Butler, A ;

Clements, J ;

Cole, J ;

Dicks, E ;

Forbes, S ;

Gorton, M ;

Gray, K ;

Halliday, K ;

Harrison, R ;

Hills, K ;

Hinton, J ;

Jenkinson, A ;

Jones, D ;

Kosmidou, V ;

Laman, R ;

Lugg, R ;

Menzies, A ;

Perry, J ;

Petty, R ;

Raine, K ;

Richardson, D ;

Shepherd, R ;

Small, A ;

Solomon, H ;

Tofts, C ;

Varian, J ;

West, S ;

Widaa, S ;

Yates, A ;

Easton, DF ;

Riggins, G ;

Roy, JE ;

Levine, KK ;

Mueller, W .

CANCER RESEARCH, 2006, 66 (08) :3987-3991

← 1 2 3 →