Despite decades of research, glioblastoma (GBM) remains very difficult to treat and there have been only marginal improvements in patient survival. Therefore, new therapeutic strategies are urgently needed. Recently, Douglas Hanahan and his colleagues have developed a novel therapeutic approach for GBM treatment in genetically engineered mouse models. Their strategy uses a combination of the antidepressant imipramine, the VEGF inhibitor bevacizumab, and an immune checkpoint inhibitor such as those targeting PD-L1. They posit that imipramine upregulates immunogenic autophagy in GBM cancer cells and reprograms tumor associated macrophages to a pro-inflammatory phenotype, while bevacizumab normalizes the tumor vasculature that leads to an influx of T cells, which are enhanced by the inclusion of an immune checkpoint inhibitor. In mouse models, this drug combination was much more effective in treating GBM than were any of the agents used alone as monotherapies.
For this ASPIRE award, the above findings will be the basis for a pilot clinical trial in GBM patients whose disease is progressing on first line therapy. In the trial, up to 13 patients will be treated with the triple combination, with a futility assessment at 6 months. Biopsies and blood samples will be collected whenever feasible, and tissue sections assessed histologically for biomarkers of target efficacy, including the abundance of CD8 and CD4 T cells and reprogramming of tumor associated macrophages. This Phase I clinical trial may provide proof of concept in humans that the novel combination of agents used here could move the needle towards improved therapies for GBM.