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

Pushan Dasgupta; Heather Lin; Gayatri Kumar; Zaid Soomro; Max M Ayala; Edwin R Parra; Shiao-Pei Weathers; Frederick F Lang; Krishna P Bhat; John de Groot; Nazanin K Majd

doi:10.1007/s11060-025-05131-9

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

J Neurooncol. 2025 Jun 25. doi: 10.1007/s11060-025-05131-9. Online ahead of print.

Authors

Pushan Dasgupta^{1

2}, Heather Lin³, Gayatri Kumar⁴, Zaid Soomro⁵, Max M Ayala⁶, Edwin R Parra⁶, Shiao-Pei Weathers⁷, Frederick F Lang^{8

9}, Krishna P Bhat⁴, John de Groot¹⁰, Nazanin K Majd¹¹

Affiliations

¹ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Pushan.dasgupta@bcm.edu.
² Department of Neurology, Baylor College of Medicine, Houston, TX, USA. Pushan.dasgupta@bcm.edu.
³ Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Research, Mayo Clinic Phoenix, Phoenix, AZ, USA.
⁵ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
¹⁰ Department of Neurological Surgery, University of California-San Francisco, San Francisco, CA, USA. john.degroot@ucsf.edu.
¹¹ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. nkmajd@mdanderson.org.

PMID: 40560330
DOI: 10.1007/s11060-025-05131-9

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.