Researchers led by Ludwig Lausanne’s Douglas Hanahan reported in September in Cancer Cell a combination of three existing drugs that significantly prolongs survival in mouse models of the lethal brain cancer glioblastoma multiforme (GBM). The drugs—the antidepressant imipramine, an anti-PD-L1 antibody and an analog of the anti-angiogenic therapy bevacizumab—synergize to unleash potent anti-tumor immune responses. Bevacizumab is known to quasi-normalize leaky tumor blood vessels, whose abnormalities compromise chemotherapy and immunotherapy. The bevacizumab analog also remodels the tumor vasculature to facilitate T cell infiltration, while imipramine hyperactivates cancer cell autophagy to stimulate anti-tumor immunity. The antidepressant, the researchers found, additionally reprograms macrophages from an M2 state, in which they promote tumor growth and survival, into an M1 state, in which they support T cell infiltration and killing of cancer cells. Remarkably, the findings implicate histamine receptor signaling in the programming of immunosuppressive macrophages—signaling activity that imipramine inhibits. GBM patients taking antihistamines had modestly better survival in a small cohort, consistent with the observed benefits of inhibiting histamine signaling in the mouse model. Together, the drugs induced potent anti-tumor immune responses and delayed tumor progression, extending survival of the mice. Added to this, the anti-PD-L1 checkpoint blockade antibody enhanced the therapeutic effects and further prolonged survival. Planning is underway for a phase I pilot trial to evaluate the drug combination in GBM patients.
Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity
Cancer Cell, 2022 September 15