Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma

Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma. We hypothesized that upfront neoadjuvant combination immunotherapy, administered with disease in situ, could induce a stronger immune response than treatment given after resection or after recurrence. Here, we present a case of newly diagnosed IDH-wild-type, MGMT promoter unmethylated GBM, treated with a single dose of neoadjuvant triplet immunotherapy (anti-programmed cell death protein 1 plus anti-cytotoxic T-lymphocyte protein 4 plus anti-lymphocyte-activation gene 3) followed by maximal safe resection 12 days later. The anti-programmed cell death protein 1 drug was bound to TILs in the resected GBM and there was marked TIL infiltration and activation compared with the baseline biopsy. After 17 months, there is no definitive sign of recurrence. If used first line, before safe maximal resection, checkpoint inhibitors are capable of immune activation in GBM and may induce a response. A clinical trial of first-line neoadjuvant combination checkpoint inhibitor therapy in newly diagnosed GBM is planned (GIANT; trial registration no. NCT06816927 ).

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Publication Details

Journal
Nature Medicine
Published
2025-02-27
DOI
https://doi.org/10.1038/s41591-025-03512-1
Citations
50
Primary Topic
Glioma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
81.27

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article

Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma

James S. Wilmott, Tri Giang Phan, Mustafa Khasraw, Yizhe Mao et al.
50 citations
Nature Medicine
Glioma Diagnosis and Treatment
81.27
article

Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma

James S. Wilmott, Tri Giang Phan, Mustafa Khasraw, Yizhe Mao, James Drummond, Alexander Maxwell Menzies, Tuba N. Gide, Xinyu Bai, Kristen J. Perry, Laveniya Satgunaseelan, Joseph H.A. Vissers, Dannel Yeo, Sean M. Grimmond, Robert V. Rawson, Nicole Caixeiro, Brindha Shivalingam, Ismael A. Vergara, Michael Back, Camelia Quek, Michael E. Buckland, Inês Pires da Silva, David A. Reardon, David M. Ashley, Helen Wheeler, Helen Rizos, Russell J. Diefenbach, Georgina Venetia Long, Elena Shklovskaya, Bart Neyns, Matteo Salvatore Carlino, Richard A. Scolyer, Edward C. Hsiao, Umaimainthan Palendira, Maria Gonzalez, John E.J. Rasko
article en
50 citations

Abstract

Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma. We hypothesized that upfront neoadjuvant combination immunotherapy, administered with disease in situ, could induce a stronger immune response than treatment given after resection or after recurrence. Here, we present a case of newly diagnosed IDH-wild-type, MGMT promoter unmethylated GBM, treated with a single dose of neoadjuvant triplet immunotherapy (anti-programmed cell death protein 1 plus anti-cytotoxic T-lymphocyte protein 4 plus anti-lymphocyte-activation gene 3) followed by maximal safe resection 12 days later. The anti-programmed cell death protein 1 drug was bound to TILs in the resected GBM and there was marked TIL infiltration and activation compared with the baseline biopsy. After 17 months, there is no definitive sign of recurrence. If used first line, before safe maximal resection, checkpoint inhibitors are capable of immune activation in GBM and may induce a response. A clinical trial of first-line neoadjuvant combination checkpoint inhibitor therapy in newly diagnosed GBM is planned (GIANT; trial registration no. NCT06816927 ).

Nature MedicineVol. 31(5)
The University of Sydney (AU), New South Wales Department of Health (AU), Mater Health Services (AU), Garvan Institute of Medical Research (AU), The University of Melbourne (AU), Duke University (US), Royal Prince Alfred Hospital (AU), Royal North Shore Hospital (AU), Centenary Institute (AU), Blacktown & Mount Druitt Hospital (AU), Westmead Hospital (AU), Chris O’Brien Lifehouse (AU), Center for Neuro-Oncology (US), Cure Brain Cancer Foundation (AU), Dana-Farber Cancer Institute (US), Melanoma Institute Australia (AU), Universitair Ziekenhuis Brussel (BE), Macquarie University (AU)
Amgen, Bristol-Myers Squibb, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Hexal AG, Regeneron Pharmaceuticals, Merck KGaA, Les Laboratories Pierre Fabre, Australian Government, Myriad Genetics, Innovent Biologics, SkylineDx, Cancer Institute NSW, Macquarie University, University of Sydney, Eisai, Servier, Melanoma Institute Australia, Qbiotics, NeraCare, Genentech, EMD Serono, Spark Therapeutics, Medical Research Council, National Health and Medical Research Council, Sydney Medical School, Sydney Medical School Foundation, Daiichi Sankyo Europe
Good health and well-being
Openalex Percentile: Top 0%
Glioma Diagnosis and Treatment
81.27
DOIOpen Access PDFOpenAlex
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