Attacking Glioblastoma by Combining Immune Checkpoint Inhibitors with Gene Therapy Looks Promising

Attacking Glioblastoma by Combining Immune Checkpoint Inhibitors with Gene Therapy Looks Promising

Attacking an aggressive brain tumor with immunostimulatory gene therapy while enhancing the immune system’s ability to fight it with immune checkpoint inhibitors might be a promising approach to treat patients with glioblastoma multiforme, a brain tumor currently associated with a very poor prognosis.

The findings from the study, “Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy,” published in Molecular Therapy, revealed that combining both these approaches in glioblastoma mice models significantly extended their survival, compared to either treatment alone.

“We hope the implementation of our gene therapy strategy for gliomas, used in combination with immune checkpoint blockade, will eventually provide successful treatment for patients with this devastating brain cancer,” Maria Castro, PhD, co-senior author and professor of neurosurgery and cell and developmental biology at the University of Michigan, said in a news release.

Recent evidence has shown that under conditions of inflammation and tumor growth, the blood-brain barrier is permeable to the passage of immune cells, suggesting that immunotherapies may show promise in treating brain cancers.

The U-M team had already developed a gene therapy for glioblastoma patients, which is currently being tested in a Phase 1 clinical trial (NCT01811992). This consists of injecting an adenovirus, which contains the genetic information for two distinct proteins, into the tumor, followed by the administration of the anti-viral ganciclovir (GCV).

The first protein, called herpes simplex virus type-I thymidine kinase (Ad-TK), converts GCV into its active metabolite, leading to tumor cell lysis and releasing tumor antigens that may be recognized by the immune system. Then the second protein, called Flt3L, helps recruit and activate tumor-killing T-cells into the tumor site.

Although this therapy has shown promise in glioblastoma models, these tumors are known to have a marked immunosuppressive environment, including the accumulation of myeloid-derived suppressor cells (MDSCs), which might reduce the effectiveness of the immunostimulatory gene therapy.

The team’s findings revealed that MDSCs constituted more than 40 percent of the tumor-infiltrating immune cells, leading them to hypothesize that MDSCs were impairing the function of tumor-specific T-cells. Indeed, the researchers found that depleting the supply of MDSCs from these mice significantly improved their survival.

“For the first time, we proved that a type of immunosuppressive cells within the tumor environment play a major role in determining the impact of immunotherapies,” Castro said.

Next, the team assessed whether boosting the immune activity using immune checkpoint inhibitors also improved the tumor response to the gene therapy. They found that combining either anti-PD-L1 or anti-CTLA-4 immune checkpoint inhibitors with the gene therapy yielded markedly better results than any of the treatments alone.

“We report much higher therapeutic efficacy in preclinical brain tumor models using the combination of both therapies, leading to an increase in median survival,” said Pedro Lowenstein, MD, PhD, and co-senior author. “This effect is not seen with either approach on its own.”

“Our work has shown that overcoming brain tumor-induced immune suppression is critical for enhancing efficacy of anti-tumor immunotherapies,” said first author Neha Kamran, PhD, a neurosurgery research fellow in the Castro/Lowenstein Lab. “This knowledge will help us in guiding the development of immunotherapies for patients with this dismal disease.”