Stereotactic radiation therapy with concurrent immunotherapy for recurrent glioblastoma—hope or hype?

See the article by Sahebjam et al in this issue pp. 677–686.

Despite recent advancements in the management of glioblastoma (GBM), outcomes remain dismal and novel strategies are badly needed. There is a recent resurgence of interest in novel immunotherapy regimens. Recurrent gliomas are considered “cold tumors” in its response to immunotherapy. Recurrent gliomas are characterized by a low mutation burden and low T-cell infiltrate. Increased infiltration of myeloid-derived suppressor cells and tumor-associated macrophages contribute to an immunosuppressive tumor microenvironment. PD-1 pathway and its ligand have an important role in tumor immune evasion in gliomas. A recent randomized, phase III CHECKMATE trial using a single-agent programmed cell death receptor (PD-1) immune checkpoint inhibitor, nivolumab was unable to show a demonstrable response compared to the single-agent bevacizumab (BEV), an anti-vascular growth factor inhibitor.¹

Preclinical evidence suggests a clear rationale for combining stereotactic radiotherapy (SRT) with immune checkpoint blockade, and these studies have shown improved overall survival (OS). Upregulated PD-L1 expression in recurrent glioma cells leads to immune evasion that may be overcome with treatment using an anti-PD-1 antibody. Preclinical evidence shows SRT increases tumor neoantigen presentation, upregulation of PD-L1 expression and the combination of SRT with immune checkpoint blockade may provide lasting antitumor immunity and immunologic memory.²

Delayed effect of SRT impacts multiple cell types in the brain and tumor microenvironment. SRT leads to endothelial cell damage and hypoxia, increase in T-cell dysfunction and microglia and macrophage activation, and increase in inflammatory cytokines all of which promote an immunosuppressive tumor microenvironment.³ Improved understanding of altered changes in the brain and tumor microenvironment following SRT are important in developing combination regimens to increase antitumor immunity overall in recurrent gliomas.³

Reported results of the phase 1 study of hypofractionated re-irradiation SRT trial and concurrent pembrolizumub (PEMBRO), a PD-1 inhibitor with BEV for recurrent high-grade gliomas (HGG) confirmed safety and tolerability of this regimen. Despite the small study size (24 patients), a median OS of 13.5 months was noted in the BEV-naïve recurrent HGG patients.⁴ In contrast, a recently reported randomized phase II of single-agent PEMBRO with/without BEV in the same patient population showed no activity.⁵

Phase I clinical translational studies are needed to answer essential questions about potential efficacy, including the optimal SRT dose and fractionation, appropriate sequencing as well as clinical efficacy of novel combinations of immunotherapy regimens with re-RT. Additional studies are testing re-irradiation SRT techniques in combination with novel immunotherapy regimens such as dual checkpoint inhibitors targeting both T-cell immunoglobulin mucin (Tim) 3 and PD-1 pathways in order to elicit a more durable immune response.⁶

Specific GBM genomic alterations including mitogen-activated protein kinase (MAPK) pathway alterations and immune infiltration may identify a select patient group responsive to the combination of immunotherapy and SRT.⁷ Translational studies including flow cytometric-based immunophenotyping and RNA sequencing of immune cells to identify activation and transcriptomic changes in the brain resident immune cells including microglia, tumor-infiltrating myeloid, and lymphoid cells following SRT are important to developing predictive biomarkers of response to SRT and concurrent immunotherapy. Until translational studies identify subgroups of patients that may benefit from combination immunotherapies regimens, we can only remain hopeful that novel treatment strategies are on the horizon.