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

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.

Keywords: brain neoplasms; immunotherapy.

Figure 1

Swimmer plot representing the survival, surgical resection extent, and last nivolumab dosing per individual patient. Each bar represents an individual patient. Patients from cohort 1 and cohort 2 are depicted by, respectively, an orange or blue bar. Gross total resection and partial resection are depicted by black square and black triangle, respectively. Last administration of nivolumab is indicated by a red square. A blue arrowhead at the end of a bar indicates patients who are still alive.

Figure 2

Case of a 42-year-old male patient with progressive disease of glioblastoma (IDH-1 wild type). The patient was diagnosed 4.5 years earlier with an anaplastic astrocytoma (WHO grade 3, IDH-1 wild type) of the left frontal lobe that was completely resected and treated with adjuvant radiation therapy with concomitant temozolomide and six cycles of adjuvant temozolomide. At first recurrence, 3 years later, was treated again with radiation therapy (60 Gy) with concomitant temozolomide and 6 cycles of adjuvant temozolomide. (A) Axial view of gadolinium-enhanced T1 MRI of the brain, 17 months after the first progression, the patient was enrolled in the study, underwent a frontal lobectomy with injection of ipilimumab (5 mg) and nivolumab (10 mg) in the brain tissue lining the resection cavity. (B) Postoperative imaging reveals limited gadolinium enhancement of the brain tissue lining the resection cavity. (C–H) Axial images of gadolinium-enhanced T1 MRI of the brain were made with a 6 weeks interval. Postoperative gadolinium enhancement at the margins of the resection cavity decreases through time. The patient remains disease-free 2.7 years after initiating study treatment. IDH-1, isocitrate dehydrogenase-1.

Figure 3

Case illustration of a 73-year-old female patient with progressive disease of glioblastoma (IDH-1 wild type) (A) Axial view of gadolinium-enhanced T1 MRI of the brain 8 months after a first complete resection followed by adjuvant radiation therapy (30×2 Gy) with concomitant temozolomide chemotherapy and six cycles of adjuvant temozolomide showing progressive disease. (B) Photograph showing a perioperative image of injection of ipilimumab (10 mg) in the brain tissue lining the resection cavity after complete resection of the tumor recurrence. (C) Postoperative axial view of gadolinium-enhanced T1 MRI of the brain showing no contrast captation. (D) Histopathological examination of the resected tissue with H&E staining confirmed a WHO grade 4 glioma. (E) Axial view of gadolinium-enhanced T1 MRI of the brain 4 months after the initiation of study treatment (patient received all 4 intravenous nivolumab administrations), revealed a thickening of the gadolinium-enhanced lining of the resection cavity with increase in perilesional edema. (F) During a neurosurgical exploration, tissue lining the resection cavity was removed and a biopsy of the underlying brain was obtained. Histopathological examination (H&E) revealed a collagenrich tissue with areas of necrosis, hemosiderin deposits, infiltrates of lymphocytic cells, thick-walled vessels with signs of fibrinoid necrosis. No evidence of glioblastoma cells was found. (G) Axial view of gadolinium-enhanced T1 MRI of the brain showing tumor progression 5 months later. The patient died of progressive disease 35 months after initiating study treatment. IDH-1, isocitrate dehydrogenase-1.

Figure 4

(A) Probability of progression-free survival according to Kaplan-Meier estimates for the study population (n=27) and a pooled historical control population (n=469) of Belgian patients with recurrent glioblastoma who were treated in three prospective phase II clinical trials and a multicenter medical need program for bevacizumab. (B) Probability of overall survival according to Kaplan-Meier estimates. (C) Probability for overall survival according to B7-H3 expression score by NanoString IO 360 gene expression profiling.

Figure 5

(A) Heat map representing NanoString IO 360 gene expression profiling sorted by B7-H3 score (each vertical line represents the scores for one glioblastoma sample/patient). (B) Immunohistochemical (IHC) staining for B7-H3 of a gliobastoma with no staining of the tumor cells, the endothelial cells of the blood vessels (BV) are positive. (C) IHC staining for B7-H3 of a glioblastoma with strong staining of the tumor cells, the endothelial cells of the BV are also positive.