Viral Mimicry May Enhance Immune Response Against Glioblastomas

New research from Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, scientists have found that targeting ZNF638, a “master regulator” protein that silences retroviruses, can induce an antiviral response in glioblastoma.

This makes immune checkpoint inhibitor (ICI) therapy more effective in treating famously difficult-to-treat glioblastomas. The protein could also serve as a biomarker for a likely positive response to immunotherapy, shaping personalized patient treatment plans.

Glioblastoma is the most common type of brain tumor in adults, with about 12,000 cases in the United States each year. Despite the disease’s prevalence, outcomes for patients with glioblastoma have barely improved in the last 20 years. With a strongly immunosuppressive microenvironment, highly variable presentations between patients and physically challenging surgical conditions, glioblastoma remains exceptionally difficult to treat.

Dr. Ashish Shah

“Brain tumors are one of the most formidable foes in medicine,” said Ashish Shah, M.D., a neurosurgeon and researcher at Sylvester and assistant professor of neurological surgery at the Miller School. “Our current treatment options are simply insufficient.”

Immune Checkpoint Inhibition Limitations

Immune checkpoint inhibition has been successfully used to treat more than a dozen diverse cancers. But because brain cancers are in such a strongly immune-suppressive environment, the treatment has largely failed in the case-by-case attempts to date.

“For many other cancers, immunotherapies have completely changed the field. But for brain tumors, we haven’t seen that same improvement,” Dr. Shah said. “At least, not yet.”

Learning what could make immune checkpoint therapies more effective — or effective at all — for glioblastoma patients is critical for understanding how to treat patients best. According to Dr. Shah’s new study, viral mimicry may be the answer.

Viral mimicry, a tool at the leading edge of cancer treatment, may be the key path forward in making immune checkpoint inhibition effective for treating glioblastoma.

The goal of viral mimicry is to trick the body into thinking the tumor has a viral infection, prompting an immune response. Over millions of years, the human genome has collected fragments of viruses called human endogenous retroviruses. Most of the time, our body silences these retroviral genes through various mechanisms, particularly the HUSH protein complex.

In viral mimicry, clinicians trigger the patient’s body to “un-silence” these inactive viral fragments. These ancient fragments are not strong enough to cause a real viral infection, but they still trigger an anti-viral immune response. That antiviral response can make tumors more susceptible to immunotherapies.

“We’re using evolution to attack tumors,” Dr. Shah said.

Viral mimicry was first successfully used to make ovarian cancer more susceptible to ICI in 2015. It has since been used in at least four other cancers, and it’s a rapidly developing area of research. But it had not been successfully applied to brain tumors until Dr. Shah’s new work.

Un-silencing Ancient Viruses

The question for Dr. Shah and his team, then, was how they could use viral mimicry to make immune checkpoint inhibitors work for glioblastoma. For that, they turned to ZNF638, a key regulator of the group of proteins that keep retroviruses silent. By suppressing ZNF638 in the tumor, they might create a viral mimicry response, opening the doors to immune checkpoint inhibitors effectively treating glioblastoma at last.

The researchers first searched cancer databases, documenting associations between ZNF638 and immune-related factors such as immune cell infiltration. They analyzed glioblastoma patients’ genetic data and found that patients who were more responsive to immune checkpoint inhibitor therapy naturally had lower expressions of ZNF638 and higher survival rates. Cell-based experiments and single-cell RNA sequencing revealed that tumors with low ZNF638 tended to have more immune cell infiltration, and the monitoring system for retroviruses was active. This ZNF638-antiviral connection was seen in published patient data, too. It was possible that targeting ZNF638 could create “viral mimicry” conditions in tumors.

Armed with these results, the researchers tested the impacts of suppressing ZNF638 in preclinical tests, targeting it only in the tumor cells and leaving healthy brain tissue untouched. Combining ZNF638 targeting with immune checkpoint inhibitor therapy improved the treatment’s efficacy. ZNF638 suppression had decreased tumor growth, increased T-cell lymphocyte infiltration and improved survival times.

Medical student Jay Chandler

“The most surprising findings were in the clinical data, where patients with low ZNF638 expression had improved responses to immunotherapy,” said Jay Chandar, a fourth-year medical student in Dr. Shah’s lab and study co-author. “That strongly supported our whole idea that knocking down ZNF638 would make tumors more susceptible to immunotherapy.”

Dr. Deepa Seetharam

“With previous trials using ICI to treat glioblastoma having largely failed, it’s exciting to find a novel therapeutic target and see that viral mimicry could help,” said Deepa Seetharam, Ph.D., a postdoctoral scholar in the Department of Neurosurgery and study co-author. “I’m optimistic this could improve prognoses for glioblastoma patients.”

The Future of Immunotherapy for Glioblastoma

The promising results point to the potential for ZNF638 to be a biomarker, shaping personalized treatment plans. Immune checkpoint inhibitors are not currently approved for treating glioblastoma, so previous patients have been on a case-by-case basis, Dr. Shah said. Using ZNF638 as a biomarker could help change that by predicting which patients would likely be responsive to ICI therapy.

While a novel biomarker is the most immediate outcome, the long-term goal remains developing a brain-penetrating drug to target ZNF638 in glioblastoma, allowing ICI to be used effectively to treat more patients.

“Then we’ll really be changing the game,” Dr. Shah said. “A synergistic treatment like that is the future of immunotherapy in treating glioblastoma.”