Treating Pediatric Brain Tumors Through Gene and Immune Therapy: A Clinical Trial Combining Checkpoint Inhibitors and Gene Therapies.
Pedro R. Lowenstein, MD; PhD, and principal investigator
In the United States, brain cancer is the main cause of cancer-related deaths in children. Approximately 16,000 children develop the disease each year and of those 2,000 will die. Pediatric brain cancer is very difficult to treat because brain tumors often cannot be completely removed surgically, cancer cells spread throughout the brain, and the tumors can be located near important functional areas. Treating a brain tumor with chemotherapy is difficult because a physical, protective barrier surrounds the brain and blocks the entry of anti-cancer chemotherapeutics from the blood into the brain. Although radiation is commonly used in adult brain cancer patients, its use in children is limited by long term damage to the developing brain. Thus, there is a great need to develop better treatments for children with brain cancer.
In our lab, we developed a novel gene therapy methodology which combines cancer cell killing genes and immune stimulatory genes to work together by attracting dendritic or messenger cells to the tumor. As the cancer killing genes work, tumor antigens are released from dying tumor cells. The dendritic cells then stimulate a systemic immune response to those tumor antigens. This anti-tumor immune response fights against the malignant brain tumor cells, and brings about the regression of the mass. In doing so, median survival is increased while anti-tumor immunology remembers the tumor cells — thereby reducing tumor recurrences without the need for further treatment.
We completed a Phase I trial of the combined administration using viral vectors that expressed both the killing gene and the immune stimulatory gene in adult patients with high grade gliomas (tumors.) The results are very encouraging. Survival was approximately 22 months with no Dose Limited Toxicities. The Maximum Tolerated Dose was not reached, indicating that the highest doses of these substances used is safe in adult human patients suffering from these tumors. To further improve the therapeutic response, we will add an immune-checkpoint inhibitor to our combined immune and gene therapy. We now plan to test our approach in the context of the pediatric population suffering from these high-grade tumors by injecting these genes into the cavity left by the surgical removal of the tumor.
After submitting the documentation to the FDA and performing any additional required experiments, we hope to receive final FDA approval of our Investigational New Drug Application as well as of our clinical protocol by the University of Michigan Institutional Review Board. Then we can implement — with the clinical team in Michigan Medicine’s Department of Neurosurgery — a Phase I/II trial. The initial Phase I trial will determine whether the combination of gene therapy and checkpoint inhibitors is safe in children, while the continuing Phase II trial will determine the efficacy of the combined therapy.