A study by Ludwig Cancer Research has identified a combination of three existing drugs that significantly prolongs survival in mouse models of deadly cancerous glioblastoma multiforme (GBM) of the brain. Researchers led by Ludwig Lausanne’s Douglas Hanahan report in the current issue of cancer cell how the drugs used in the combination — an antidepressant, an immune checkpoint-blocking antibody, and a mouse analog of a cancer therapy that, by themselves, provide no survival benefit against GBM — synergize to trigger powerful therapeutic immune responses against the tumor.
“Our investigation illustrates the great potential of drug redirection for cancer treatment,” said Hanahan, Distinguished Researcher at the Ludwig Institute for Cancer Research, Lausanne Branch. “We have shown here that three extensively characterized drugs already in clinical use can be novelly combined to overcome the tumor’s immunosuppressive barrier and induce a therapeutic immune response that significantly prolongs survival in mouse models of GBM, a cancer that has up to present escaped all the therapies used to treat it. »
Hanahan and her colleagues explored in preclinical studies whether drug combinations that target distinct tumor growth-promoting properties might work synergistically to block or reverse disease progression. Previous studies in Hanahan’s lab had shown that a generic “tricyclic” antidepressant, imipramine, could be used in combination with an anticoagulant drug to hyperactivate a process known as autophagy, in which cells cannibalize their own proteins and organelles for the nutrients needed to sustain their growth. Hyperactivation of autophagy by these drugs slightly prolonged the survival of mice with GBM.
In this study, researchers tested whether a drug targeting an unrelated phenomenon, abnormal blood vessels in tumors, when used in combination with imipramine could further improve outcomes. They used a mouse analog of the human anti-VEGF antibody bevacizumab, which has been approved as a second-line treatment for GBM, but not so much to prolong survival as to relieve patients by relieving edema caused by aberrant vascularization. Bevacizumab is known to nearly normalize leaky tumor blood vessels, the abnormalities of which also compromise both chemotherapy and immunotherapy.
The researchers found that the combination of imipramine and the VEGF-blocking antibody significantly delayed tumor progression and increased survival times in mice with GBM. The combination, they found, disrupts tumor immune defenses via multiple mechanisms, triggering a potent anti-tumor immune response characterized by the recruitment of helper and cytotoxic T cells, which are essential for anti-tumor immunity.
A human-specific bevacizumab analog that targets the angiogenic factor VEGF in mice has been shown to remodel tumor blood vessels in a manner known to promote T-cell infiltration. At the same time, hyperactivation of imipramine autophagy stimulated anti-tumor immunity.
But that was not all. Hanahan and her team found that the antidepressant also has a distinct and unintended effect on a type of immune cell known as a macrophage, which is found in high numbers in GBM tumors. It turns out that imipramine also targets a biochemical signaling pathway that helps keep macrophages in a so-called “M2” state, in which they support tumor growth. Blocking this signal with the antidepressant reprogrammed them into an “M1” state that promotes T cell infiltration and destruction of cancer cells.
Yet, although this drug combination prolonged survival, its effects were not very long-lasting. Hanahan and his team, however, saw an opportunity in his reconditioning of the tumor’s immune microenvironment. To capitalize on this opportunity, they added a checkpoint-blocking antibody to the mix that amplifies anti-tumor immune responses.
Such treatments have so far failed miserably against GBM in humans. But when added to the bevacizumab-imipramine combination, an anti-PD-L1 antibody drug significantly prolonged survival in mice.
“Since each of these therapies is already in clinical use,” Hanahan said, “they wouldn’t have to go through the tedious pharmacological development and safety testing required for new drugs. For this reason, we hope that the combination therapy we have identified in this study can be tested relatively soon in human clinical trials for GBM, an extremely aggressive cancer for which there is a desperate need for new treatment strategies. . »
Indeed, planning is already underway for a Phase I pilot trial to evaluate the drug combination. If it receives regulatory approval, the trial will be led by Hanahan and Andreas Hottinger of the Center Hospitalier Universitaire Vaudois in Lausanne.
This study was supported by Ludwig Cancer Research, the European Research Council, the Swiss Federal Institute of Technology Lausanne (EPFL), the Barrow Neurological Institute, the Health Foundation, the Swiss Foundation for Cancer Research and the Netherlands organization for scientific research.
Hanahan is also Emeritus Professor and former Director of the Swiss Institute for Experimental Cancer Research (ISREC) at the Swiss Federal Institute of Technology Lausanne (EPFL).