TRANSLATIONAL RESEARCH-02 THE KEYSTONE CYTOKINE, INTERLEUKIN-6, A KEY TARGET AND “ORGANIZING PRINCIPLE” FOR GLIOBLASTOMA THERAPY: A DECADE OF TRANSLATIONAL PROGRESS FROM GENOMICS TO THE LABORATORY AND TO A MULTICENTER CLINICAL TRIAL

Interleukin-6 (IL-6), the ‘keystone cytokine’, affects homeostatic processes, including innate and adaptive immunity, and is regarded as a prominent target for clinical intervention (Hunter, 2015). IL-6 is also a senescence-associated-gene (SAG), linked to cellular aging, the aging brain, and cancer pathogenesis. We hypothesized that SAGs, including IL-6, are overexpressed in older patients, in higher grades of glioma, portending a poor prognosis (Coppola, 2014). Indeed, in an analysis of 47 gliomas at the Moffitt Cancer Center, we found that the ‘senescence score’ composed of genes central to the pathogenesis of glioma, defined a novel signature, provided prognostic biomarkers as well as targets for drug discovery and immunotherapy (Coppola, 2014). We suggested that IL-6 could be linked to neoplastic transformation and could be predictive of glioma progression (US Patent #8741575). At the University of Pennsylvania, we found an inhibitor of IL-6 to be well-tolerated in patients with glioblastoma undergoing CAR T cell therapy (O’Rourke, 2017). Yi Fan’s team discovered (Wang, 2018) that targeting IL-6 led to a remarkable change in the tumor microenvironment (TME), with a “switch” from the M2 (immunosuppressive, pro-tumorigenic) macrophage phenotype to an immunostimulatory (M1) phenotype, resulting in a significant increase in survival. Adding CD40 agonist enhanced the activity of infiltrated T cells, and an almost complete cure in GBM models. The use of immune checkpoint inhibitors in these experiments and by others (Lamano, 2019) produced a significant increase in survival. These findings led to a multicenter trial (PI, Stephen Bagley; NCT 047299959), by NRG Oncology (BN010), combining IL-6 inhibition (tocilizumab), PD-L1 blockade (atezolizumab) and stereotactic radiotherapy to treat recurrent glioblastoma. More recently, a MDACC team discovered that IL-6 blockade not only promotes tumor immunity but also abrogates the toxicity of checkpoint blockade, decoupling the autoimmune toxicity while promoting tumor immunity through the IL-12 pathway (Hailemichael, 2022).