University of Florida researchers have received approval from the Food and Drug Administration to test an investigational new therapy in a first-in-human clinical trial for participants with primary glioblastoma, the most aggressive malignant brain tumor.
The Phase I trial, expected to begin this fall and enroll 24 patients over age 18, will be led by Dr. Jianping Huang, and Dr. Ashley Ghiaseddin, of the Lillian S. Wells Department of Neurosurgery. The trial is expected to last three years.
The trial builds upon preclinical research by Huang and team that demonstrated a novel technique using the injection of genetically modified cells to enhance the effectiveness of a form of immunotherapy known as chimeric antigen receptor therapy, or CAR T-cell therapy, in targeting glioblastoma.
Using treatment-resistant tumor models in cells and mice, the team showed that using modified cells may reverse immunosuppression triggered by a tumor, thus enhancing the effectiveness of therapy to halt or even shrink tumor growth and potentially yield long-term protection.
In the upcoming human trial, researchers aim to test the safety and feasibility of the technique. They will use a participant’s own blood cells, genetically modify them outside the body and then re-infuse them. Prior to receiving the one-dose treatment, participants will undergo conventional treatments including chemotherapy and radiation. The trial will include only participants with a primary glioblastoma tumor that expresses a protein called CD70.
“We will modify immune cells called T cells using CAR T-cell therapy so they have the ability to recognize and kill the tumor,” said Dr. Linchun Jin, an assistant scientist in Huang’s group who led the preclinical study. “Usually, the T cells in glioblastoma patients’ blood don’t recognize the tumor, but they are able to recognize it after we educate them in the laboratory.”
The technique involves co-opting the release of a protein molecule called interleukin-8, or IL-8, which acts as a kind of ‘GPS honing signal’ for CAR T cells expressing the IL-8 receptor, Huang said.
“This allows T cells to know where the tumor is located and precisely target the tumor zone, which can minimize potential toxicity and enhance antitumor efficacy in patients treated with the CAR T cells,” Huang said. “Our results show that the IL-8 receptor-modified CAR T cells resulted in a complete response in mice and provided lasting protection from tumor re-growth.”
She said she anticipates the technique will be tested in additional clinical trials in the future.“Importantly, this new technology holds potential to possibly alter the course of many other cancers, such as acute myeloid leukemia and osteosarcomas,” Huang said. The trial marks the fourth time that UF has brought a novel therapeutic for malignant brain tumors from preclinical studies to human clinical trial, said Dr. Duane Mitchell, co-director of UF’s Preston A. Wells Jr. Center for Brain Tumor Therapy and the Phyllis Kottler Friedman Professor in the Lillian S. Wells Department of Neurosurgery.
The CAR T cell research reached the clinical-trial level with the support of UF’s Powell Gene Therapy Center, regulatory and clinical neuro-oncology teams, the UF Health Cancer Center, the UF Clinical and Translational Science Institute and the UF College of Medicine, he said.
“Dr. Huang and her team’s extraordinary efforts, in collaboration with clinical leaders in our brain tumor center and the outstanding experts in cell therapy manufacturing at UF, has positioned our institution at the forefront in the advancement of novel cancer immunotherapy approaches,” said Mitchell, associate director of innovation and discovery at the UF Health Cancer Center and director of the UF Clinical and Translational Science Institute.
The preclinical studies and the clinical trial are supported by the U.S. Department of Defense, the UF Health Cancer Center and under a broader $12 million gift from The Harris Rosen Foundation to advance innovative brain tumor immunotherapy research and care at UF Health and support the UF-led ReMission Alliance Against Brain Tumors, a network of experts from top peer institutions and vested collaborators affected by brain cancer.