Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency.
Clicks: 214
ID: 274997
2022
Article Quality & Performance Metrics
Overall Quality
Improving Quality
0.0
/100
Combines engagement data with AI-assessed academic quality
Reader Engagement
Emerging Content
9.6
/100
32 views
32 readers
Trending
AI Quality Assessment
Not analyzed
Abstract
Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.
| Reference Key |
das2022genomicnature
Use this key to autocite in the manuscript while using
SciMatic Manuscript Manager or Thesis Manager
|
|---|---|
| Authors | Das, Anirban;Sudhaman, Sumedha;Morgenstern, Daniel;Coblentz, Ailish;Chung, Jiil;Stone, Simone C;Alsafwani, Noor;Liu, Zhihui Amy;Karsaneh, Ola Abu Al;Soleimani, Shirin;Ladany, Hagay;Chen, David;Zatzman, Matthew;Cabric, Vanja;Nobre, Liana;Bianchi, Vanessa;Edwards, Melissa;Sambira Nahum, Lauren C;Ercan, Ayse B;Nabbi, Arash;Constantini, Shlomi;Dvir, Rina;Yalon-Oren, Michal;Campino, Gadi Abebe;Caspi, Shani;Larouche, Valerie;Reddy, Alyssa;Osborn, Michael;Mason, Gary;Lindhorst, Scott;Bronsema, Annika;Magimairajan, Vanan;Opocher, Enrico;De Mola, Rebecca Loret;Sabel, Magnus;Frojd, Charlotta;Sumerauer, David;Samuel, David;Cole, Kristina;Chiaravalli, Stefano;Massimino, Maura;Tomboc, Patrick;Ziegler, David S;George, Ben;Van Damme, An;Hijiya, Nobuko;Gass, David;McGee, Rose B;Mordechai, Oz;Bowers, Daniel C;Laetsch, Theodore W;Lossos, Alexander;Blumenthal, Deborah T;Sarosiek, Tomasz;Yen, Lee Yi;Knipstein, Jeffrey;Bendel, Anne;Hoffman, Lindsey M;Luna-Fineman, Sandra;Zimmermann, Stefanie;Scheers, Isabelle;Nichols, Kim E;Zapotocky, Michal;Hansford, Jordan R;Maris, John M;Dirks, Peter;Taylor, Michael D;Kulkarni, Abhaya V;Shroff, Manohar;Tsang, Derek S;Villani, Anita;Xu, Wei;Aronson, Melyssa;Durno, Carol;Shlien, Adam;Malkin, David;Getz, Gad;Maruvka, Yosef E;Ohashi, Pamela S;Hawkins, Cynthia;Pugh, Trevor J;Bouffet, Eric;Tabori, Uri; |
| Journal | Nature Medicine |
| Year | 2022 |
| DOI |
10.1038/s41591-021-01581-6
|
| URL | |
| Keywords |
Citations
No citations found. To add a citation, contact the admin at info@scimatic.org
Comments
No comments yet. Be the first to comment on this article.