TRLR-02 Targeting Glioblastoma Microenvironment to Unleash Immune Forces

Abstract Brain cancer has persistently eluded therapeutic advances over the past three decades. Here, we aim to raise awareness of the potential differences between the cancer microenvironment within the brain vs. peripheral organ cancers, which may contribute to the therapeutic setbacks observed in brain cancer treatment. While the blood-brain barrier has long been implicated in drug impermeability, its impact on brain cancer may extend far beyond mere drug exclusion. Studies have shown that soluble factors such as VEGF are more concentrated in brain cancer than in any other malignancies. Moreover, recent studies revealed that VEGF, TWEAK, and others can also press on the immune brakes. Therefore, we hypothesize that normalizing the tumor microenvironment could pave the way for effective therapeutic interventions, especially immunotherapy. Our in vitro studies confirmed abundant production of VEGF by glioblastoma 1 (GBM1) cell line, which is exceptionally well scavenged by the anti-VEGF antibody – bevacizumab. Moreover, in vitro, co-culture of T cells and GBM1 cell line without vascular component demonstrated no therapeutic activity of bevacizumab or typical immunotherapeutic drug – anti-PD1 checkpoint inhibitor – nivolumab given in monotherapies. However, a combination of both antibodies revealed therapeutic efficacy in a dose-dependent manner in our experimental system. Currently, intravenous delivery of bevacizumab is the standard of care in patients with glioblastoma recurrence, but its effectiveness has not been proven in this group of patients. Intravenous nivolumab failed in clinical trials. Based on our observations and the negligible penetration of antibodies to the brain, we hypothesize that transiently opening the blood-brain barrier may be necessary to enhance antibody delivery to the tumor microenvironment, alleviate immune suppression, and unlock immune cell activity. Therefore, achieving high antibody concentrations in brain cancer tissue, coupled with a combination of classic checkpoint inhibitors with scavengers of soluble immunosuppressive molecules, could herald a new era of brain cancer therapy.