Abstract
| Original language | English |
|---|---|
| Article number | 352 |
| Journal | Nature communications |
| Volume | 12 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Dec 2021 |
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In: Nature communications, Vol. 12, No. 1, 352, 01.12.2021.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy
AU - Gromeier, Matthias
AU - Brown, Michael C.
AU - Zhang, Gao
AU - Lin, Xiang
AU - Chen, Yeqing
AU - Wei, Zhi
AU - Beaubier, Nike
AU - Yan, Hai
AU - He, Yiping
AU - Desjardins, Annick
AU - Herndon, James E.
AU - Varn, Frederick S.
AU - Verhaak, Roel G.
AU - Zhao, Junfei
AU - Bolognesi, Dani P.
AU - Friedman, Allan H.
AU - Friedman, Henry S.
AU - McSherry, Frances
AU - Muscat, Andrea M.
AU - Lipp, Eric S.
AU - Nair, Smita K.
AU - Khasraw, Mustafa
AU - Peters, Katherine B.
AU - Randazzo, Dina
AU - Sampson, John H.
AU - McLendon, Roger E.
AU - Bigner, Darell D.
AU - Ashley, David M.
N1 - Funding Information: The results shown here are based in part upon data generated by TCGA Research Network (https://cancergenome.nih.gov). Special acknowledgement to Susan Boulton, Chevelle Bullock, Christina Cone, Brian Crouch, Elena Dobrikova, Kristen Foss, Rachel Hesler, Jenny Jackman, Zachary McKay, Elizabeth Miller, Christopher Pirozzi, Stevie Threatt, and Matthew Waitkus (Duke University), and to Alan Chang, Aly Khan, Catherine Igartua, Denise Lau, and Jason Perera (TEMPUS, Inc.). We thank the members of the Data and Safety Monitoring Board: John M. Cunningham (University of Chicago, Chicago, IL), A. William Blackstock, Jr (Wake Forest University, Winston-Salem, NC), Michael Vogelbaum (Cleveland Clinic, Cleveland, OH), Kenneth R. Hess (MD Anderson, Houston, TX), Jeremy Rich (University of California San Diego, La Jolla, CA), Ryan J. Sullivan (Massachusetts General Hospital, Boston, MA); and the trial participants and their families. This work was supported by grants from The Brain Tumor Research Charity, Jewish Communal Fund, Circle of Service Foundation, Uncle Kory Foundation, Department of Defense (W81XWH-16-1-0354), and NIH grants R35CA197264, P01CA154291, P50CA190991, R01NS108773, R01NS099463, R21NS112899, P01CA225622, and F32CA224593. Support was also received through the Angels Among Us fundraising event and a gift from the Asness Family both in support of Brain Tumor Research. Funding Information: M.G., M.C.B., A.D., D.P.B., H.S.F., S.K.N., J.H.S., D.D.B., and D.M.A. own intellectual property related to PVSRIPO, which has been licensed to Istari Oncology, Inc. M.G., A.D., D.P.B, A.H.F., H.S.F., and D.D.B. hold equity in Istari Oncology, Inc. M.G., D.P.B., and D.D.B. are paid consultants of Istari Oncology, Inc. A.D. is on the advisory board of Orbus Therapeutics and receives research support from Orbus Therapeutics, Sympho-gen, Celgene, Bristol-Myers Squibb. H.Y. receives royalties from Genetron, Agios Pharmaceuticals, and Personal Genome Diagnostics (PGDX); he is CSO with owner interest in Genetron Holdings. M.K. receives institutional research funding from AbbVie, Bristol-Myers Squibb, and Specialized Therapeutics, and honoraria for consultancy/ advisory roles with AbbVie, Bristol-Myers Squibb, Eli Lilly, Ipsen, Pfizer, and Roche. J.H.S. has an equity interest in Annias Immunotherapeutics, which has licensed intellectual property from Duke related to the use of the pepCMV vaccine in the treatment of GBM. J.H.S. is an inventor on patents related to PEP-CMV DC vaccine with tetanus, as well as PVSRIPO and D2C7 in the treatment of GBM. If the technology is commercially successful in the future, Dr. Sampson (and any other conflicted individuals on the manuscript) and Duke may benefit financially. The remaining authors declare no competing interests. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10–20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.
AB - Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10–20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.
UR - http://www.scopus.com/inward/record.url?scp=85099416307&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-020-20469-6
DO - https://doi.org/10.1038/s41467-020-20469-6
M3 - Article
C2 - 33441554
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 352
ER -