Analyzing Tumor Treating Fields (TTFields) therapy concomitantly with checkpoint inhibitors in a GBM mouse model

Glioblastoma (GBM) is the most common malignant form of adult brain tumor, with a median survival of around 1.5-2 years. Despite multimodal treatments (tumor resection, radiotherapy, and chemotherapy) achieving an effective cure remains a significant challenge due to its highly aggressive nature. Immune checkpoint inhibitors have emerged as a promising strategy to combat GBM; however, limitations have hindered clinical success, largely due to the “cold” and immunosuppressive tumor microenvironment (TME). Tumor Treating Fields (TTFields) therapy is a non-invasive, FDA approved treatment for GBM that employs specific frequency ranges (100-500 kHz) delivered through transducer arrays placed on the head. Our initial in vitro studies, using the inovitro system, confirmed that TTFields (72 hours, 200kHz) enhanced the immune response in GBM by inducing immunogenic cell death, which led to the recruitment of immune cells through the release of damage-associated molecular patterns (DAMPs). Additionally, we demonstrated that TTFields increased T-cell activity (IFNgamma and perforin) and enhanced the motility and phagocytic activity in antigen presenting cells (Raw 264.7) and dendritic cells (JawsII). We then studied the therapeutic potential of directly applying the TTFields (10-14 days, 200kHz), using the inovivo system, to an orthotopic syngeneic GBM mouse model (CT2A-luciferase) with the checkpoint inhibitor anti-PD-1 . Consistent with previous findings, the single arm treatments of TTFields and anti-PD-1 reduced tumor volume and slightly modulated the immune environment. Concomitant treatment of TTFields with systemic anti-PD-1 therapy reduced tumor volume and significantly increased immunomodulation, as observed via an increase in T cells and myeloid cells. Our findings suggest that concomitant treatment of TTFields with checkpoint inhibitors has the potential to help transform GBM into a “hot” tumor, making it an attractive target for immunotherapy.