Intraventricular Delivery of Engineered Oncolytic Herpes Simplex Virotherapy to Treat Localized and Metastatic Pediatric Brain Tumors

Principal Investigator: FRIEDMAN, GREGORY K
Program: PRCRP
Proposal Number: CA140089
Award Number: W81XWH-15-1-0108
Funding Mechanism: Career Development Award
Partnering Awards:
Award Amount: $529,196.79


Current therapies for childhood brain tumors like surgery, chemotherapy, and radiation are very damaging to the developing brain of a child and can result in significant long-term brain injury and hormone dysfunction. Approximately 25% of children with brain cancer do not survive. Therefore, novel therapies that target tumor cells while sparing normal cells are desperately needed. Genetically altered herpes simplex virus, which has been used safely and effectively in adult trials and is being prepared for a pediatric trial at the University of Alabama at Birmingham (UAB), offers an inventive, targeted, less-toxic approach for children with incurable brain tumors and may be beneficial as an added therapy for curable tumors allowing for lower doses of traditional therapies and less toxicity. Currently, the virus is injected directly into the tumor. This requires an invasive neurosurgical procedure and limits the ability for repeat injections of the virus that might be beneficial in preventing tumor recurrence.

Our objective, which has the potential to radically improve this novel therapy, is to develop a unique route of delivery of the virus into the spinal fluid. This would have a significant impact on pediatric brain tumor patients by removing the need for an invasive neurosurgical procedure, permitting repeat dosing of the virus to maximize its ability to kill cancer cells, and enabling the targeting of tumor in the brain and tumor that has spread to the spine, which can occur in aggressive pediatric brain tumors. Because injecting the virus into the spinal fluid may cause toxicity, we propose to identify the cause of any toxicity and develop strategies to prevent any harm. We will also test the ability of the virus, when injected into the spinal fluid, to target and kill pediatric medulloblastoma, the most common malignant brain cancer in children. Accomplishing these studies will greatly enhance our knowledge of how the virus works in the spinal fluid, how the immune system responds to virus in the spinal fluid, and ways in which commercially available drugs can be used to lessen any toxicity from the virus. The knowledge gained from these studies will be used to advance this innovative route of delivering the virus to clinical trials in children with brain tumors and to develop improved viruses. Since the virus has already been used in clinical trials, we expect to be able to translate the proposed research to new clinical trials as soon as safety is confirmed in the proposed studies.

A childhood brain tumor diagnosis is devastating for military families. The disruption caused by the diagnosis and frequent treatments may result in a parent being pulled off a deployment and may limit the career of military personnel. This proposed project seeks to expand treatment options by improving the delivery and development of a novel, targeted therapy, which may improve outcomes and reduce toxicity in children with brain tumors, thereby benefiting active duty Service members and their families.

Dr. Friedman specializes in the care of pediatric brain tumor patients and conducting pediatric brain tumor research. His primary goal is to improve outcomes for children with brain cancer by developing and improving novel, targeted therapies like genetically altered herpes simplex virus in the lab and then translating these therapies to clinical trials to benefit children with brain tumors. This Career Development Award will provide Dr. Friedman with every opportunity to become a leading pediatric brain tumor researcher by providing critical mentorship from Drs. Markert and Gillespie, both international leaders in virus therapy and brain tumor research who have successfully mentored many young investigators. The key components of the career development plan include: (1) frequent face-to-face interaction with mentors to discuss research goals and strategies, review lab data, problem-solve any issues, and teach Dr. Friedman various experimental techniques and approaches; (2) establishment of a mentoring committee to review Dr. Friedman's progress, identify barriers and recommend strategies to overcome any present and potential problems; (3) continued education and advancement of Dr. Friedman's clinical expertise; (4) development of both local and national collaborations with other investigators to help advance the research; and (5) hands-on training for obtaining the necessary regulatory approval from the U.S. Food and Drug Administration and the UAB Institutional Review Board to conduct clinical trials with new, experimental therapies.