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Cited by 113Glioma Diagnosis and TreatmentCancer Immunotherapy and BiomarkersImmunotherapy and Immune Responses

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial

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Duerinck, Johnny, Schwarze, Julia Katharina, Awada, Gil, Tijtgat, Jens, Vaeyens, Freya, Bertels, Cleo, Geens, Wietse, Klein, Samuel +13 more·2021·Journal for ImmunoTherapy of Cancer
DOI 10.1136/jitc-2020-002296PMC PMC8231061
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Abstract

Background: Patients with recurrent glioblastoma (rGB) have a poor prognosis with a median overall survival (OS) of 30–39 weeks in prospective clinical trials. Intravenous administration of programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors has low activity in patients with rGB. In this phase I clinical trial, intracerebral (IC) administration of ipilimumab (IPI) and nivolumab (NIVO) in combination with intravenous administration of NIVO was investigated. Methods: Within 24 hours following the intravenous administration of a fixed dose (10 mg) of NIVO, patients underwent a maximal safe resection, followed by injection of IPI (10 mg; cohort-1), or IPI (5 mg) plus NIVO (10 mg; cohort-2) in the brain tissue lining the resection cavity. Intravenous administration of NIVO (10 mg) was repeated every 2 weeks (max. five administrations). Next generation sequencing and RNA gene expression profiling was performed on resected tumor tissue. Results: Twenty-seven patients were enrolled (cohort-1: n=3; cohort-2: n=24). All patients underwent maximal safe resection and planned IC administrations and preoperative NIVO. Thirteen patients (cohort-1: n=3; cohort-2: n=10) received all five postoperative intravenous doses of NIVO. In cohort-2, 14 patients received a median of 3 (range 1–4) intravenous doses. Subacute postoperative neurological deterioration (n=2) was reversible on steroid treatment; no other central nervous system toxicity was observed. Immune-related adverse events were infrequent and mild. GB recurrence was diagnosed in 26 patients (median progression-free survival (PFS) is 11.7 weeks (range 2–152)); 21 patients have died due to progression. Median OS is 38 weeks (95% CI: 27 to 49) with a 6-month, 1-year, and 2-year OS-rate of, respectively, 74.1% (95% CI: 57 to 90), 40.7% (95% CI: 22 to 59), and 27% (95% CI: 9 to 44). OS compares favorable against a historical cohort (descriptive Log-Rank p>0.003). No significant difference was found with respect to PFS (descriptive Log-Rank test p>0.05). A higher tumor mRNA expression level of B7-H3 was associated with a significantly worse survival (multivariate Cox logistic regression, p>0.029). Conclusion: IC administration of NIVO and IPI following maximal safe resection of rGB was feasible, safe, and associated with encouraging OS. Trial registration: NCT03233152 .

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  • Intracerebral injections are clinically feasible and are performed in a variety of clinical scenarios and preclinical settings.

    “Intracerebral injections are clinically feasible, and are performed in a variety of clinical scenarios (17–23), as well as in various preclinical settings (4, 24–27).”

    From Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection (2023) · cites this paper as [23]

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Authors
Duerinck, J., Schwarze, J. K., Awada, G., Tijtgat, J., Vaeyens, F., Bertels, C., Geens, W., Klein, S., Seynaeve, L., Cras, L., D’Haene, N., Michotte, A., Caljon, B., Salmon, I., Bruneau, M., Kockx, M., Van Dooren, S., Vanbinst, A.-M., Everaert, H., Forsyth, R., & Neyns, B.
Affiliations
  • Vrije Universiteit Brussel (BE)
  • Université Libre de Bruxelles (BE)
  • Cell Carta NV, Antwerp, Belgium
  • Centre for Medical Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
Corresponding author
Neyns, Bart
ORCID
Venue
Journal for ImmunoTherapy of Cancer
Publisher
BMJ
Published
2021-06
Volume
9
Issue
6
Pages
e002296
ISSN
2051-1426 (ISSN-L)
DOI
10.1136/jitc-2020-002296
PMC
PMC8231061
OpenAlex
W3174938876
Cited by
113
References
7
Citations by year
2026: 20 · 2025: 20 · 2024: 34 · 2023: 25 · 2022: 11 · 2021: 3
FWCI
10.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • VUBIR (Vrije Universiteit Brussel) (acceptedVersion, other-oa)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders
  • Paul De Knop steunfonds [https://www.vub.be/foundation/fondsen/vub-uzb-paul-de-knop-fonds#vub-uzb-paul-de-knop-fonds] (Not applicable)
  • Financial support was obtained from two non-for-profit entities
  • Stichting Tegen Kanker (2016-128)
Topics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
recurrent glioblastoma, intracerebral administration, CTLA-4 blockade, anti-PD-1 therapy, ipilimumab, nivolumab, immune checkpoint inhibitors, combination immunotherapy, maximal safe resection, progression-free survival, overall survival, immune-related adverse events, tumor gene expression profiling, central nervous system toxicity, brain metastases, glioma stem cells, tumor-infiltrating lymphocytes, tumor-infiltrating macrophages, tumor-infiltrating neutrophils, tumor-infiltrating T cells, tumor-infiltrating B cells, tumor-infiltrating NK cells, tumor-infiltrating dendritic cells, tumor-infiltrating myeloid cells, tumor-infiltrating Treg cells, tumor-infiltrating Th1 cells
MeSH terms
Adult, Aged, Antibodies, Monoclonal, Female, Glioblastoma, Humans, Immunotherapy, Male, Middle Aged, Survival Analysis, CTLA-4 Antigen

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