Advancing immune forces at the tumor frontlines

In the darkest enclaves of the human body, the immune system wages a silent war to prevent cancer. An army of immune cells, including T effector and natural killer cells, act as frontline soldiers in an ongoing battle. But cancer cells are stealthy. Eventually, malignant cells neutralize the immune system’s efforts by suppressing the immune response and developing immune tolerance (1).

Immunotherapy enlists a biomolecular cavalry to reactivate the immune system’s anticancer offensive. Some cancers build resistance to immunotherapy, and others such as ovarian cancer respond poorly or not at all (2). Researchers are zeroing in on the body’s epigenome — the molecular elements that turn genes on and off — as an additional force to revive the previously repressed battalion of immune cells. Targeting epigenetic modifiers using epigenetic inhibitors or hypomethylating agents is a promising option for treating immunotherapy resistant cancers.

In a recent study published in The Journal of Clinical Investigation, researchers led by Daniela Matei, an oncologist and ovarian cancer researcher at Northwestern University, tested guadecitabine, a hypomethylating agent that targets the cancer cell epigenome and activates immune cells to boost their receptivity to immunotherapy in end stage ovarian cancer patients (3). “Most patients with ovarian cancer eventually reach this point where treatments are limited and their survival is less than a year,” said Matei.

Cancer cells carry tumor antigens on their surfaces that the immune system recognizes. Eventually, tumors supress these surface antigens to evade the immune response. “We try to remove that veil and make the tumors recognizable by the immune system,” Matei explained.

In a Phase 2 clinical trial, Matei explored if treating patients with the epigenetic inhibitor guadecitabine, followed by pembrolizumab, a common immune checkpoint inhibitor drug that blocks proteins that suppress the immune response, would provide a therapeutic benefit to patients with ovarian cancer. She and her team hypothesized that guadecitabine may reverse the DNA methylation marks that tumors use to bypass the immune system. Priming tumors in this way would make ovarian tumors, which are usually unreceptive to immunotherapy, responsive to chemotherapy treatment.

Matei’s team evaluated cancer progression and epigenetic and immune status in patients by analyzing tumor biopsies, blood plasma, and peripheral blood mononuclear cells before and after the combination therapy. Of the 35 patients eligible for evaluation, eight had stable disease and three responded partially to the dual therapy. “Even though we didn't have a lot of [responders], we had patients with stable disease for more than six months. It's not perfect, but it was a desirable outcome,” said Matei. After treatment, these patients carried changes in their methylomes and transcriptomes that indicated antitumor immune response activation.

Matei’s findings address an unmet need for ovarian cancer patients and may help researchers identify the mechanisms that underly immune cell reactivation and predict which patients will respond to treatment. “If you can identify these individuals, you're going to enrich some patients’ lives,” said Stephen Baylin, an epigeneticist at the Johns Hopkins University School of Medicine who was not involved in this study.

However, timing is important. Combining epigenetic therapy and immunotherapy at an earlier disease stage may improve patient outcomes. “Patients who had advanced disease often had multiple treatments [that] caused abnormal epigenetic changes,” said Baylin. “[Epigenetic drugs] would be much more effective therapies if we didn't wait for such advanced disease or resistance to previous therapies.”