PD-L1/PD-1 Axis in Glioblastoma Multiforme

Glioblastoma (GBM) is the most popular primary central nervous system cancer and has an extremely expansive course. Aggressive tumor growth correlates with short median overall survival (OS) oscillating between 14 and 17 months. The survival rate of patients in a three-year follow up oscillates around 10%. The interaction of the proteins programmed death-1 (PD-1) and programmed cell death ligand (PD-L1) creates an immunoregulatory axis promoting invasion of glioblastoma multiforme cells in the brain tissue. The PD-1 pathway maintains immunological homeostasis and protects against autoimmunity. PD-L1 expression on glioblastoma surface promotes PD-1 receptor activation in microglia, resulting in the negative regulation of T cell responses. Glioblastoma multiforme cells induce PD-L1 secretion by activation of various receptors such as toll like receptor (TLR), epidermal growth factor receptor (EGFR), interferon alpha receptor (IFNAR), interferon-gamma receptor (IFNGR). Binding of the PD-1 ligand to the PD-1 receptor activates the protein tyrosine phosphatase SHP-2, which dephosphorylates Zap 70, and this inhibits T cell proliferation and downregulates lymphocyte cytotoxic activity. Relevant studies demonstrated that the expression of PD-L1 in glioma correlates with WHO grading and could be considered as a tumor biomarker. Studies in preclinical GBM mouse models confirmed the safety and efficiency of monoclonal antibodies targeting the PD-1/PD-L1 axis. Satisfactory results such as significant regression of tumor mass and longer animal survival time were observed. Monoclonal antibodies inhibiting PD-1 and PD-L1 are being tested in clinical trials concerning patients with recurrent glioblastoma multiforme.

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A stratified phase II study of cetuximab for the treatment of recurrent glioblastoma multiforme: Preliminary results

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.1558 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 1558-1558 ◽

Cited By ~ 7

Author(s):

J. Sadones ◽

C. Chaskis ◽

E. J. Joosens ◽

L. A. Dhondt ◽

J. Baurain ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Phase Ii ◽

Phase Ii Study ◽

Gene Copy Number ◽

Growth Factor Receptor ◽

Recurrent Glioblastoma ◽

Gene Copy ◽

Recurrent Glioblastoma Multiforme ◽

Egfr Gene ◽

Recurrent Gbm

1558 Background: The Epidermal Growth Factor Receptor (EGFR) gene is frequently amplified and mutated in high-grade gliomas. We are investigating the activity of the EGFR-targeted monoclonal antibody cetuximab for the treatment of patients (pts) with recurrent glioblastoma multiforme (GBM) following surgery, radiotherapy and chemotherapy. Methods: Adult pts with recurrent GBM are allocated to two parallel treatment strata according to the amplification status of the EGFR gene (determined by FISH). According to a Simon two-stage phase II study design 1 response in 13 pts/stratum is required to continue recruitment and complete the second stage of pt recruitment. Cetuximab is administered at 400 mg/m2 (2 hour infusion) day 1 and 250 mg/m2 day 8 and for all subsequent weekly doses (1 hour infusion). Results: Between May and December 2005, 17 pts were recruited (10 without EGFR-ampl, 4 with EGFR-ampl and 3 under investigation); 4F/13M; median age 51 years, range 32–67). Recruitment is ongoing. Sixteen pts initiated study treatment; 1 pt withdrew consent before the initiation of therapy. Treatment related toxicity in the first 94 treatment cycles consisted of grade 1/2 folliculitis/dermitis in all treated pts. Grade 3 adverse events consisted of thrombocytopenia (n=1 pt), diminished consciousness (n=1 pt), dizziness/confusion (n=1 pt), infectious bronchopneumonia (n=1 pt), and infectious cellulitis (n=1 pt). Thirteen pts have been evaluated for response ≤ week 8 of study treatment. Eleven pts had progression of disease. Two patients had SD at 8 weeks (follow-up is ongoing). Conclusions: These preliminary data suggest that cetuximab can be safely administered to pretreated patients with recurrent GBM. Updated results regarding safety and activity as well as a correlative study of EGFR and PTEN expression and gene copy number of the GBM and response to cetuximab will be presented at the meeting. No significant financial relationships to disclose.

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Bevacizumab-induced isolated oculomotor nerve palsy in glioblastoma multiforme

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211066888 ◽

2021 ◽

pp. 107815522110668

Author(s):

Ezgi Değerli ◽

Gülin Alkan ◽

Nihan Şentürk Öztaş ◽

Şahin Bedir ◽

Sümeyra Derin ◽

...

Keyword(s):

Side Effects ◽

Glioblastoma Multiforme ◽

Cranial Nerve ◽

Nerve Palsy ◽

Growth Factor Receptor ◽

Recurrent Glioblastoma ◽

Oculomotor Nerve ◽

Oculomotor Nerve Palsy ◽

Recurrent Glioblastoma Multiforme ◽

Systemic Side Effects

Introduction: Bevacizumab, a monoclonal antibody against the vascular endothelial growth factor receptor, is the standard treatment of recurrent glioblastoma multiforme. In addition to common systemic side effects of bevacizumab, there are rare cases of cranial nerve palsy. Case report: We report a case of transient oculomotor nerve palsy after systemic administration of bevacizumab. Twenty-four hours after the systemic infusion of bevacizumab, transient oculomotor nerve palsy developed in a 49-year-old male patient. In the cranial MRI, there was no malignancy-related progression. Management and outcome: Bevacizumab treatment was discontinued. Methylprednisolone was started considering that bevacizumab increased the inflammatory response. Oculomotor nerve palsy resolved in 14 days. Discussion: There are many side effects of bevacizumab whose mechanisms of action have not been fully explained. Cranial nerve involvement is rarely reported. Our case is the first reported case of bevacizumab-induced oculomotor nerve palsy.

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