Ipilimumab and Bevacizumab in Glioblastoma

Abstract

The median survival in glioblastoma is just over a year, with no standard second-line therapy. Ipilimumab is an immune checkpoint inhibitor that activates the anti-tumour immune response by cytotoxic T-lymphocyte antigen-4 blockade. There is significant evidence supporting its role in the treatment of malignant melanoma, including in patients with brain metastases. The addition of the anti-angiogenesis agent, bevacizumab, seems to offer additional benefit and limit the immune-related side-effects of ipilimumab in melanoma. To date there have been no clinical trials investigating this combination in glioblastoma. In this single practice case series, 20 patients with glioblastoma were consented for and treated with ipilimumab and bevacizumab in combination. Safety, tolerability and the response to treatment were reviewed for all patients. Three patients were treated after palliative first-line radiotherapy, one patient after first-line chemoradiation and 16 patients were treated with recurrent disease. Sixty-five per cent of patients completed four cycles of 3 weekly ipilimumab therapy, administered with 2 weekly bevacizumab. Radiographic responses for patients with recurrent disease were evaluated by Response Assessment in Neuro-oncology (RANO) criteria; 31% of patients showed a partial response, 31% had stable disease and 38% had disease progression. The treatment combination was well tolerated, with treatment terminated before completion due to adverse events in two patients. Autoimmune toxicity was manageable with systemic corticosteroid therapy. Ipilimumab and bevacizumab in combination show promising activity with a predictable and manageable toxicity profile, warranting further clinical studies.

The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment

“…In a cohort of patients with advanced melanoma, pre-treatment serum levels of VEGF-A correlated with poor overall survival and poor response to immune checkpoint therapy with ipilimumab (229). Initial promising results have been reported in phase I clinical trials combining ipilimumab and the anti-VEGF-A antibody bevacizumab in advanced melanoma and glioblastoma (109, 117). This combination appears safe and well tolerated (109, 117) and warrants further investigation and comparison to current treatment regimens.…”

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma

“…However, despite some promising pre-clinical results (5, 133,134), early studies with pD1, pDL1 or cTLA4 inhibitors against GBM have, at least as monotherapy, not yet fulfilled this promise (120,(135)(136)(137)(138)(139). Grossauer et al noted that neither cTLA4 inhibition nor pD1 inhibition increased efficacy against GBM when used as monotherapy (120).…”

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

“…At the moment there are FDAapproved monoclonal antibodies directed against distinct inhibitory molecules such as ipilimumab targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), nivolumab and pembrolizumab targeting programmed cell death 1 (PD-1) and atezolizumab targeting programmed cell death ligand 1 (PD-L1), and many others are in development. The great success of immune checkpoint inhibitors in a therapy of a number of advanced solid tumor type1 leading to the evaluation of these compounds in CNS gliomas, including GBM (122,123).…”