CHAD CARR PEDIATRIC BRAIN TUMOR CENTER | MICHIGAN MEDICINE

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.

https://medicine.umich.edu/dept/pediatric-brain-tumor-research-initiative

Long-term goal is to improve understanding of tumor metabolism to design more effective therapies.
Long-term goal is to improve understanding of tumor metabolism to design more effective therapies.
New biorepository will provide the technology to grow and store cancer cells for use in brain tumor research.
New biorepository will provide the technology to grow and store cancer cells for use in brain tumor research.
Together, these Atlanta institutions pioneer the use of nanotechnology to gauge tumor size, stop tumor growth, and shrink tumors.
Together, these Atlanta institutions pioneer the use of nanotechnology to gauge tumor size, stop tumor growth, and shrink tumors.
Research focused on uncovering the mechanisms by which gene fusions contribute to tumor formation in pediatric low grade gliomas.
Research focused on uncovering the mechanisms by which gene fusions contribute to tumor formation in pediatric low grade gliomas.
Objective is to determine if an electrical stimulations regimen can arrest the division of dividing brain tumor cells.
Objective is to determine if an electrical stimulations regimen can arrest the division of dividing brain tumor cells.
Working to find biomarkers for brain tumors to make the diagnosis of tumor types easier, track their growth or even, no recurrence.
Working to find biomarkers for brain tumors to make the diagnosis of tumor types easier, track their growth or even, no recurrence.
Research establishing the feasibility of using interstitial infusion for treating pediatric brain stem gliomas. FDA approved clinical trial underway.
Research establishing the feasibility of using interstitial infusion for treating pediatric brain stem gliomas. FDA approved clinical trial underway.
Research focused on proteins which are active in pediatric low-grade gliomas. From this research, NYU hopes to better select molecular targeted drugs directed at these pathways.
Research focused on proteins which are active in pediatric low-grade gliomas. From this research, NYU hopes to better select molecular targeted drugs directed at these pathways.
Research focused on using new brain imaging techniques to improve diagnosis, prognosis and treatment of pediatric brain tumors.
Research focused on using new brain imaging techniques to improve diagnosis, prognosis and treatment of pediatric brain tumors.
Partnership between a physician and research scientist is examining innovative drug delivery methods for children with brain tumors.
Partnership between a physician and research scientist is examining innovative drug delivery methods for children with brain tumors.
This groundbreaking project could be the first step for the development of a variety of attractive modalities targeting therapeutic approaches beyond immunotherapy.
This groundbreaking project could be the first step for the development of a variety of attractive modalities targeting therapeutic approaches beyond immunotherapy.
Discovery regarding cancer cells' ability to hijack the brain's nerves could lead to new treatment avenues for aggressive brain tumors.
Discovery regarding cancer cells' ability to hijack the brain's nerves could lead to new treatment avenues for aggressive brain tumors.
Developing a strategy to ensure rapid translation of new drug candidates into clinical trials of medulloblastomas is a collaborative effort.
Developing a strategy to ensure rapid translation of new drug candidates into clinical trials of medulloblastomas is a collaborative effort.
University of Michigan Researchers aim to treat Pediatric Brain Tumors through the combination of Gene and Immune Therapy.
University of Michigan Researchers aim to treat Pediatric Brain Tumors through the combination of Gene and Immune Therapy.
Researchers at Johns Hopkins All Children’s and Johns Hopkins University hypothesize that a group of lncRNAs, including lncRNA HLX2-7, are key molecular signatures (biomarkers) and therapeutic targets for Group III medulloblastoma in children.
Researchers at Johns Hopkins All Children’s and Johns Hopkins University hypothesize that a group of lncRNAs, including lncRNA HLX2-7, are key molecular signatures (biomarkers) and therapeutic targets for Group III medulloblastoma in children.
Scientists work to establish a new system for targeting oncogenic mutations in pediatric brain tumors.
Scientists work to establish a new system for targeting oncogenic mutations in pediatric brain tumors.
Through a new collaboration between Duke and UNC Chapel Hill, our team is working on a radical new approach that combines living tissue brain slices with patient biopsies to recapitulate the clinical brain cancer phenotype.
Through a new collaboration between Duke and UNC Chapel Hill, our team is working on a radical new approach that combines living tissue brain slices with patient biopsies to recapitulate the clinical brain cancer phenotype.