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Combined immunother...
Combined immunotherapy improves outcome for replication repair deficient (RRD) high-grade glioma failing anti-PD1 monotherapy: A report from the International RRD Consortium.
- Article/chapterEnglish2024
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LIBRIS-ID:oai:gup.ub.gu.se/330985
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https://gup.ub.gu.se/publication/330985URI
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https://doi.org/10.1158/2159-8290.CD-23-0559DOI
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Immune-checkpoint inhibition (ICI) is effective for replication-repair deficient, high-grade gliomas (RRD-HGG). Clinical/biologic impact of immune-directed approaches after failing ICI-monotherapy are unknown. We performed an international study on 75 patients treated with anti-PD1; 20 are progression-free (median follow-up: 3.7-years). After 2nd-progression/recurrence (n=55), continuing ICI-based salvage prolonged survival to 11.6-months (n=38; p<0.001), particularly for those with extreme mutation burden (p=0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and immune-microenvironment. Response to re-irradiation was explained by an absence of deleterious post-radiation indel signatures (ID8). Increased CTLA4-expression over time, and subsequent CTLA4-inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to reinvigoration of peripheral immune and radiological responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/ synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology.
Subject headings and genre
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Fernandez, Nicholas R
(author)
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Levine, Adrian
(author)
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Bianchi, Vanessa
(author)
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Stengs, Lucie K
(author)
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Chung, Jiil
(author)
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Negm, Logine
(author)
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Dimayacyac, Jose Rafael
(author)
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Chang, Yuan
(author)
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Nobre, Liana
(author)
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Ercan, Ayse B
(author)
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Sanchez-Ramirez, Santiago
(author)
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Sudhaman, Sumedha
(author)
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Edwards, Melissa
(author)
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Larouche, Valerie
(author)
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Samuel, David
(author)
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Van Damme, An
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Gass, David
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Ziegler, David S
(author)
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Bielack, Stefan S
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Koschmann, Carl
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Zelcer, Shayna
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Yalon-Oren, Michal
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Campino, Gadi Abede
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Sarosiek, Tomasz
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Nichols, Kim E
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Loret De Mola, Rebecca
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Bielamowicz, Kevin
(author)
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Sabel, Magnus,1966Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för pediatrik,Institute of Clinical Sciences, Department of Pediatrics(Swepub:gu)xsabma
(author)
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Frojd, Charlotta A
(author)
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Wood, Matthew D
(author)
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Glover, Jason M
(author)
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Lee, Yi-Yen
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Vanan, Magimairajan
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Adamski, Jenny K
(author)
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Perreault, Sebastien
(author)
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Chamdine, Omar
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Hjort, Magnus Aasved
(author)
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Zapotocky, Michal
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Carceller, Fernando
(author)
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Wright, Erin
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Fedorakova, Ivana
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Lossos, Alexander
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Tanaka, Ryuma
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Osborn, Michael
(author)
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Blumenthal, Deborah T
(author)
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Aronson, Melyssa
(author)
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Bartels, Ute
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Huang, Annie
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Ramaswamy, Vijay
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Malkin, David
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Shlien, Adam
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Villani, Anita
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Dirks, Peter B
(author)
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Pugh, Trevor J
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Getz, Gad
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Maruvka, Yosef E
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Tsang, Derek S
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Ertl-Wagner, Birgit
(author)
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Hawkins, Cynthia
(author)
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Bouffet, Eric
(author)
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Morgenstern, Daniel A
(author)
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Tabori, Uri
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Göteborgs universitetInstitutionen för kliniska vetenskaper, Avdelningen för pediatrik
(creator_code:org_t)
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In:Cancer discovery14:2, s. 258-2732159-8290
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Das, Anirban
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Fernandez, Nicho ...
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Levine, Adrian
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Bianchi, Vanessa
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Stengs, Lucie K
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Chung, Jiil
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Negm, Logine
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Dimayacyac, Jose ...
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Chang, Yuan
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Nobre, Liana
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Ercan, Ayse B
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Sanchez-Ramirez, ...
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Sudhaman, Sumedh ...
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Edwards, Melissa
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Larouche, Valeri ...
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Samuel, David
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Van Damme, An
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Gass, David
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Ziegler, David S
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Bielack, Stefan ...
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Koschmann, Carl
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Zelcer, Shayna
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Yalon-Oren, Mich ...
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Campino, Gadi Ab ...
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Sarosiek, Tomasz
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Nichols, Kim E
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Loret De Mola, R ...
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Bielamowicz, Kev ...
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Sabel, Magnus, 1 ...
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Frojd, Charlotta ...
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Wood, Matthew D
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Glover, Jason M
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Lee, Yi-Yen
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Vanan, Magimaira ...
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Adamski, Jenny K
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Perreault, Sebas ...
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Chamdine, Omar
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Hjort, Magnus Aa ...
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Zapotocky, Micha ...
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Carceller, Ferna ...
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Wright, Erin
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Fedorakova, Ivan ...
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Lossos, Alexande ...
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Tanaka, Ryuma
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Osborn, Michael
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Blumenthal, Debo ...
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Aronson, Melyssa
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Bartels, Ute
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Huang, Annie
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Ramaswamy, Vijay
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Malkin, David
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Shlien, Adam
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Villani, Anita
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Dirks, Peter B
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Pugh, Trevor J
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Getz, Gad
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Maruvka, Yosef E
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Tsang, Derek S
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Ertl-Wagner, Bir ...
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Hawkins, Cynthia
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Bouffet, Eric
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Morgenstern, Dan ...
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Tabori, Uri
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MEDICAL AND HEAL ...
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Cancer discovery
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University of Gothenburg