Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium

被引：22

作者：

Das, Anirban ^{[1
,2
,3
,4
,5
,47
]}

Fernandez, Nicholas R. ^{[2
,3
]}

Levine, Adrian ^{[6
,7
]}

Bianchi, Vanessa ^{[2
,3
]}

Stengs, Lucie K. ^{[2
,3
]}

Chung, Jiil ^{[2
,3
]}

Negm, Logine ^{[2
,3
]}

Dimayacyac, Jose Rafael ^{[2
,3
]}

Chang, Yuan ^{[2
,3
]}

Nobre, Liana ^{[1
,2
,3
]}

Ercan, Ayse B. ^{[2
,3
,8
]}

Sanchez-Ramirez, Santiago ^{[2
,3
]}

Sudhaman, Sumedha ^{[2
,3
]}

Edwards, Melissa ^{[2
,3
]}

Larouche, Valerie ^{[9
]}

Samuel, David ^{[10
]}

Van Damme, An ^{[11
]}

Gass, David ^{[12
]}

Ziegler, David S. ^{[13
,14
]}

Bielack, Stefan S. ^{[15
]}

Koschmann, Carl ^{[16
]}

Zelcer, Shayna ^{[17
]}

Yalon-Oren, Michal ^{[18
]}

Campino, Gadi Abede ^{[18
]}

Sarosiek, Tomasz ^{[19
]}

Nichols, Kim E. ^{[20
]}

De Mola, Rebecca Loret ^{[21
]}

Bielamowicz, Kevin ^{[22
]}

Sabel, Magnus ^{[23
,24
]}

Frojd, Charlotta A. ^{[25
]}

Wood, Matthew D. ^{[26
]}

Glover, Jason M. ^{[27
]}

Lee, Yi-Yen ^{[28
]}

Vanan, Magimairajan ^{[29
,30
]}

Adamski, Jenny K. ^{[31
]}

Perreault, Sebastien ^{[32
]}

Chamdine, Omar ^{[33
]}

Hjort, Magnus Aasved ^{[34
]}

Zapotocky, Michal ^{[35
]}

Carceller, Fernando ^{[36
,37
]}

Wright, Erin ^{[38
]}

Fedorakova, Ivana ^{[39
]}

Lossos, Alexander ^{[40
]}

Tanaka, Ryuma ^{[41
]}

Osborn, Michael ^{[42
]}

Blumenthal, Deborah T. ^{[43
]}

Aronson, Melyssa ^{[44
]}

Bartels, Ute ^{[1
,5
]}

Huang, Annie ^{[1
,3
]}

Ramaswamy, Vijay ^{[1
,3
]}

机构：

[1] Hosp Sick Children, Div Haematol Oncol, Toronto, ON, Canada

[2] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON, Canada

[3] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada

[4] Tata Med Ctr, Dept Paediat Haematol & Oncol, Kolkata, India

[5] Univ Toronto, Dept Paediat, Toronto, ON, Canada

[6] Hosp Sick Children, Dept Paediat Lab Med, Toronto, ON, Canada

[7] Univ Toronto, Fac Med, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[8] Univ Toronto, Inst Med Sci, Fac Med, Toronto, ON, Canada

[9] Univ Laval, Pediat Haematol Oncol Dept, CHU Quebec, Quebec City, PQ, Canada

[10] Valley Childrens Hosp, Dept Paediat Oncol, Madera, CA USA

[11] Catholic Univ Louvain, St Luc Univ Hosp, Dept Paediat Haematol & Oncol, Brussels, Belgium

[12] Atrium Hlth Levine Childrens Hosp, Charlotte, NC USA

[13] Sydney Childrens Hosp, Kids Canc Ctr, Randwick, NSW, Australia

[14] UNSW Sydney, Sch Clin Med, Sydney, NSW, Australia

[15] Klinikum Stuttgart, Ctr Childhood Adolescent & Womens Med, Stuttgart Canc Ctr, Dept Pediat Oncol Hematol & Immunol, Stuttgart, Germany

[16] Univ Michigan, Pediat Hematol Oncol, CS Mott Childrens Hosp, Ann Arbor, MI USA

[17] London Hlth Sci Ctr, Dept Pediat, London, ON, Canada

[18] Sheba Med Ctr, Dept Paediat Haematol Oncol, Ramat Gan, Israel

[19] Lux Med Onkol, Warsaw, Poland

[20] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN USA

[21] Oregon Hlth & Sci Univ, Portland, OR USA

[22] Univ Arkansas Med Sci, Arkansas Childrens Hosp, Dept Pediat, Sect Pediat Hematol Oncol, Little Rock, AR USA

[23] Univ Gothenburg, Dept Paediat, Inst Clin Sci, Sahlgrenska Acad, Gothenburg, Sweden

[24] Sahlgrens Univ Hosp, Queen Silvia Childrens Hosp, Gothenburg, Sweden

[25] Sahlgrens Univ Hosp, Dept Oncol, Gothenburg, Sweden

[26] Oregon Hlth & Sci Univ, Neuropathol, Dept Pathol, Portland, OR USA

[27] Randall Childrens Hosp, Dept Pediat Hematol Oncol, Portland, OR USA

[28] Taipei Vet Gen Hosp, Neurol Inst, Dept Neurosurg, Taipei, Taiwan

[29] CancerCare Manitoba, Pediat Hematol Oncol, Winnipeg, MB, Canada

[30] Univ Manitoba, CancerCare Manitoba Res Inst, Pediat & Child Hlth, Winnipeg, MB, Canada

[31] Birmingham Childrens Hosp, Neurooncol Div, Birmingham, W Midlands, England

[32] CHU St Justine, Neurosci Dept, Child Neurol Div, Montreal, PQ, Canada

[33] King Fahad Specialist Hosp Dammam, Pediat Hematol Oncol, Dammam, Eastern Provinc, Saudi Arabia

[34] St Olavs Univ Hosp, Dept Paediat Haematol & Oncol, Trondheim, Norway

[35] Charles Univ Prague, Univ Hosp Motol, Fac Med 2, Dept Paediat Haematol & Oncol, Prague, Czech Republic

[36] Royal Marsden NHS Fdn Trust, Paediat & Adolescent Neurooncol & Drug Dev, London, England

[37] Inst Canc Res, Div Clin Studies, London, England

[38] Akron Childrens Hosp, Div Neurooncol, Akron, OH USA

[39] Univ Childrens Hosp, Clin Pediat Oncol & Hematol, Banska Bystrica, Slovakia

[40] Hadassah Hebrew Univ Med Ctr, Leslie & Michael Gaffin Ctr Neurooncol, Dept Oncol, Jerusalem, Israel

[41] Med Coll Wisconsin, Dept Pediat, Div Hematol Oncol Blood & Marrow Transplantat, Milwaukee, WI USA

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

[43] Tel Aviv Univ, Sackler Fac Med, Tel Aviv Med Ctr, Neurooncol Serv, Tel Aviv, Israel

[44] Mt Sinai Hosp, Zane Cohen Ctr Digest Dis, Toronto, ON, Canada

[45] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[46] Hosp Sick Children, Div Neurosurg, Toronto, ON, Canada

[47] Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON, Canada

[48] Princess Margaret Canc Ctr, Ontario Inst Canc Res, Toronto, ON, Canada

[49] Broad Inst Harvard & MIT, Cambridge, MA USA

[50] Technion Israel Inst Technol, Tel Aviv, Israel

来源：

CANCER DISCOVERY | 2024年 / 14卷 / 02期

关键词：

IMMUNE CHECKPOINT INHIBITION; COMBINED NIVOLUMAB; PD-1; BLOCKADE; FOLLOW-UP; IPILIMUMAB; MUTATIONS; GLIOBLASTOMA; RESISTANCE; SURVIVAL; TUMOR;

D O I：

10.1158/2159-8290.CD-23-0559

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.7 years). After second 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 the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide a 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.

引用

页码：258 / 273

页数：16

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