A Phase I Trial of VEGF-A Inhibition Combined with PD-L1 Blockade for Recurrent Glioblastoma

Abstract

Purpose:The treatment of glioblastoma (GBM) poses challenges. The use of immune checkpoint inhibition (ICI) has been disappointing as GBM is characterized by low mutational burden and low T-cell infiltration. The combination of ICI with other treatment modalities may improve efficacy. Patients and Methods:Patients with recurrent GBM were treated with avelumab, a human IgG1 antibody directed against PD-L1 (part A), or avelumab within a week after laser interstitial thermal therapy (LITT) and continuation of avelumab (part B). Bevacizumab was allowed to be combined with ICI to spare steroid use. The primary objective was to characterize the tolerability and safety of the regimens. The secondary objectives included overall survival, progression-free survival (PFS), signatures of plasma analytes, and immune cells. Results:A total of 12 patients (median age 64, range 37-73) enrolled, five in part A and seven in part B. Two serious adverse events occurred in the same patient, LITT treated, not leading to death. The median survival (OS) from enrollment was 13 months [95% CI, 4-16 months] with no differences for Part A or B. The median PFS was three months [95% CI, 1.5-4.5 months]. The decrease in MICA/MICB, gamma-delta T cells, and CD4+ T cell EMRA correlated with prolonged survival. Conclusions:Avelumab was generally well-tolerated. Adding bevacizumab to ICI may be beneficial by lowering cytokine and immune cell expression. The development of this combinatorial treatment warrants further investigation. Exploring the modulation of adaptive and innate immune cells and plasma analytes as biomarker signatures may instruct future studies in this dismal refractory disease.

Targeting of endothelial cells in brain tumours

“…This triple therapy increased the number of cytotoxic T lymphocytes, associated negatively with the numbers of myeloid‐derived suppressors and regulatory T cells in the GBM microenvironment 115 . A Phase I trial indicated that the addition of bevacizumab to ICIs might be beneficial by reducing cytokine and immune cell expression in recurrent GBM, suggesting that bevacizumab exerts a modulatory effect on immune cells and related cytokines, which can enhance the effect of ICIs 99 . Gutin et al.…”

“…115 A Phase I trial indicated that the addition of bevacizumab to ICIs might be beneficial by reducing cytokine and immune cell expression in recurrent GBM, suggesting that bevacizumab exerts a modulatory effect on immune cells and related cytokines, which can enhance the effect of ICIs. 99 Gutin et al demonstrated that patients with GBM tolerate the combination of bevacizumab and hypofractionated stereotactic radiation therapy (hfSRT) well. 116 Sahebjam et al 117 showed that the use of pablizumab, a PD-1 inhibitor, combined with hfSRT and bevacizumab treatment, is also well tolerated in patients with recurrent GBM or mesenchymal astrocytoma.…”