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. 2025 Oct;175(1):453-461.
doi: 10.1007/s11060-025-05131-9. Epub 2025 Jun 25.

Molecular and clinical determinants of response to checkpoint inhibitor immunotherapy in glioblastoma

Pushan Dasgupta  1   2 , Heather Lin  3 , Gayatri Kumar  4 , Zaid Soomro  5 , Max M Ayala  6 , Edwin R Parra  6 , Shiao-Pei Weathers  7 , Frederick F Lang  8   9 , Krishna P Bhat  4 , John de Groot  10 , Nazanin K Majd  11
Affiliations

Molecular and clinical determinants of response to checkpoint inhibitor immunotherapy in glioblastoma

Pushan Dasgupta et al. J Neurooncol. 2025 Oct.

Abstract

Purpose: While checkpoint inhibitor therapy (CPI) has transformed treatment in multiple solid tumors, its efficacy in glioblastoma (GBM) remains limited. Understanding the molecular and clinical factors that influence glioblastoma's response to CPI is essential to improving outcomes.

Methods: We identified patients with recurrent GBM, who had been treated with CPI and determined the association between their molecular, clinical, and demographic characteristics and survival outcomes.

Results: We identified 35 patients with recurrent GBM treated with CPI. PIK3CA mutation was associated with a statistically significant shorter OS duration, calculated from CPI initiation (p-value = 0.014). Tumor tissue without the mutation had less PD-1 expression in CD3+/CD8 + T cells. RB1 and TERT promoter mutations were associated with shorter PFS durations (p-value = 0.009, 0.053, respectively). Length of CPI therapy of more than 6 months was associated with increased PFS and OS (p-value = 0.069, 0.088, respectively), while steroid use at baseline was associated with a shorter OS (p-value = 0.0016). Multifocal disease was associated with shorter PFS and OS durations (p-value = 0.0011, 0.0015, respectively) among all patients.

Conclusions: In glioblastoma, PIK3CA, RB1, TERT promoter mutations, steroid use prior to start of CPI, and multifocal disease may be associated with a poor response to CPI while increased length of CPI may be associated with improved response. Our results may provide the rationale for clinical trials combining PI3K inhibitors with CPI in glioblastoma. The small sample size and retrospective nature of the study carries selection bias and/or confounding effects and larger studies need to be done to validate these results.

Keywords: PIK3CA; Checkpoint inhibitor; Glioblastoma; High-grade glioma; Immunotherapy.

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Conflict of interest statement

Declarations. Ethics approval: This study was approved by MD Anderson’s institutional review board. Consent to participate: Not required. Consent to publish: Not required. Prior presentation: American Academy of Neurology 2022 Annual Meeting Oral Presentation. Competing interests: The authors declare no competing interests.

References

    1. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant Temozolomide for glioblastoma. N Engl J Med 352(10):987–996. https://doi.org/10.1056/NEJMoa043330 - DOI - PubMed
    1. Robert C (2020) A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun 11(1):3801. https://doi.org/10.1038/s41467-020-17670-y - DOI - PubMed - PMC
    1. Soffietti R, Ahluwalia M, Lin N, Rudà R (2020) Management of brain metastases according to molecular subtypes. Nat Rev Neurol 16(10):557–574. https://doi.org/10.1038/s41582-020-0391-x - DOI - PubMed
    1. Hargadon KM, Johnson CE, Williams CJ (2018) Immune checkpoint Blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol Sep 62:29–39. https://doi.org/10.1016/j.intimp.2018.06.001 - DOI
    1. Callahan MK, Wolchok JD, Allison JP (2010) Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. Semin Oncol Oct 37(5):473–484. https://doi.org/10.1053/j.seminoncol.2010.09.001 - DOI

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