A Deadly Duo: Gene Therapy, Immunotherapy Combination to Treat Glioblastoma

Immune checkpoint blockade and gene therapy more effective together than alone in brain cancer.

A 2-pronged treatment approach shows promise in glioblastoma, according to a study published in Molecular Therapy.

Brain tumors are difficult to treat, and pose many challenges for oncologists. Furthermore, the median survival rate for patients with glioblastoma is only 14.2 months.

New research shows that combining gene therapy, to attack the tumor, and immunotherapy, to enhance the body’s own immune system, is a more effective approach in treating the disease.

“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 devastating brain cancer,” said co-senior author Maria Castro, PhD.

Unfortunately, cancer cells are able to escape fighter T cells by tricking the immune system. However, cancer immunotherapy reactivates the immune system so the T cells can recognize cancer cells and attack.

“Immune checkpoint inhibitors amplify T cell responses and are currently being tested in the clinic to increase T cell-mediated tumor killing,” said co-senior author Pedro Lowenstein, MD, PhD.

The investigators determined that the accumulation of immunosuppressive cells, called MDSCs, in the glioma environment is one of the ways glioblastomas block the immune system. For the study, the authors sought to deplete the large supply of MDSCs to determine whether it would allow immune-mediated gene therapy to eradicate glioblastoma in the mouse models.

“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.

According to the study, the investigators combined the immune checkpoint blockade approach with gene therapy. First, they injected adenovirus vectors that carried herpes simplex 1 thymidine kinase into the tumor, followed by an antiviral to elicit tumor cell death. The investigators used this in combination with another adenovirus vector carrying the protein cytokine, to recruit immune cells inside the tumor.

The results of the study showed that the gene therapy had stronger results when it was used in combination with the depletion of immunosuppressive cells from the tumor mass or with immune checkpoint blockade.

To insert mutated genes (involved in cancer) into stem cells in the brains of new born mice, the investigators used a technique called “Sleeping Beauty.” The cancer stem cells were then used to create preclinical models of relevant human glioblastoma, according to the study.

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

To implement this approach, the authors said it would require gene therapy delivered at the time of surgery with systemic delivery of the immune checkpoint inhibitors, such as via IV injection.

“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. “This knowledge will help us in guiding the development of immunotherapies for patients with this dismal disease.”

Currently, a clinical trial is being conducted at the University of Michigan in adults with glioblastoma to test a combination approach, but with a different form of immunosuppressive treatment.