Glioma-05 a novel concept for treatment of glioblastoma: vagus nerve electrical stimulation for suppression of cytokine (il-6) signaling

Abstract Glioblastoma is an aggressive, incurable cancer. Innovative approaches are urgently needed. There is resurgent interest in harnessing the power of the immune system (O’Rourke DM, 2017; Liau LM, 2023). Glioblastoma is a key target for cytokine reprogramming of the tumor microenvironment involving macrophages, monocytes, lymphocytes, and myeloid-derived cells. Furthermore, as with other cancers, the incidence and poor prognosis is linked to the age of the patient, and chronic, low-grade inflammation, or “inflammaging” (Franceschi, 2014). There is strong clinical, genomic (Coppola, 2014), preclinical data linking the progression of glioblastoma to the cytokine, IL-6. Yi Fan and colleagues (Wang, 2018; Yang, 2021) showed that blockade of IL-6 increases survival in mouse models of glioblastoma, an effect enhanced with the use of immune checkpoint blockade (ICB). These results were validated and extended by others (Tsukamoto, 2018; Lamano,2019). Taken together, we translated the findings to a prospective, multicenter clinical trial (NRG BRAIN-010, NCT04729959; PI, Stephen Bagley) for recurrent glioblastoma, combining stereotactic radiosurgery, IL-6R blockade (tocilizumab) and ICB (atezolizumab). To date, the regimen is well-tolerated with an acceptable safety profile. Vagus nerve stimulation is FDA-approved for control of medically refractory epilepsy. It is currently being evaluated in a multicenter, pivotal trial to treat advanced rheumatoid arthritis (RESET-RA, NCT04539964). Electrical stimulation of the vagus nerve activates the inflammatory reflex (Kelly, 2022), with a reduction of inflammatory cytokines, including IL-6 (Koopman, 2016). Electrical stimulation of the vagus nerve uses the ‘inflammatory reflex’ and exploits the cholinergic effect on T-cells (Levine, 2020). Taken together, we now propose a clinical trial to assess the safety and efficacy of vagal nerve stimulation for patients with glioblastoma and are in discussion with industry (SetPoint Medical) to design a prospective, clinical trial for treatment of glioblastoma.