Gene-mediated cytotoxic immunotherapy in pediatric patients with recurrent malignant brain tumors
Pediatric brain tumors are the leading cause of cancer-related death in children. Children and adolescents with relapsed or refractory brain tumors have a low likelihood of long-term survival, and new therapies are desperately needed. Modifying or stimulating a patient’s immune system has been found to be a strategy to treat certain cancers, with some of these treatments even leading to cures. Unfortunately, the use of immunotherapy for many cancers, including aggressive brain tumors, has proven difficult so far for many reasons. One barrier is that most brain tumors have an immune environment that prevents their recognition as “foreign” by the patient’s immune system. Here, we propose the translation of a two-vector viral-based immunotherapy strategy into a first-in-pediatrics phase 1 clinical trial. When this therapy has been studied in our laboratory in mice with high-grade glioma, the mice live longer and some mice were cured. The two viral vectors used here encode a cell-killing component (thymidine kinase) and an immune stimulatory component (Flt3L). When these are injected into the where the tumor was just removed during a surgery and the patient takes the antiviral medication (valacyclovir), cells with the thymidine kinase vector die and cells express Flt3L, stimulating important antigen-presenting immune cells (dendritic cells). This therapy was tested in a safety (phase 1) study in adults and was found to be safe and well-tolerated in patients with high-grade glioma.
Project Goal:
Our first goal is to conduct a phase 1 clinical trial for pediatric patients with relapsed, high-grade (non-brainstem) brain tumors who require surgery at the time of study participation to determine the doses of the viral vectors that are safe and determine how well this therapy is tolerated. At the time of surgery, any extra tumor tissue will be collected in this study to test the baseline immune status of the patients’ tumors. During the clinical trial, blood samples and spinal fluid samples will be collected at multiple timepoints (when the patient would already undergo clinical testing of blood/spinal fluid). These samples will allow us to complete our second goal, which is to determine the local and systemic changes that occur to the immune system after this immunotherapy is administered. This testing will be done via a variety of techniques, looking at blood,spinal fluid, and tumor tissue, as available. Achieving these goals will allow us to understand the effects of this dual vector immunotherapy in pediatric patients with high-risk brain tumors and, if safe and there is evidence of immune changes, may support further clinical development of this therapy in a phase 2 study.
