SGT-53, a Novel Nanomedicine that Crosses the BBB, Augments Immunotherapeutic Response in Pediatric Brain Cancers
Abstract
Brain cancer is the deadliest cancer in children (PRCRP Topic Area); more children succumb to these types of tumors than any others. Currently available treatment requires aggressive surgical resection, radiation treatment, and intensive chemo- or targeted therapy; this often causes lifelong permanent deficits in learning, impairments in growth and development, and other effects that severely impact quality of life. More effective, less damaging treatments are desperately needed to bridge the gap in treatment for children with brain cancer. There is a very important protein present in normal cells called p53, the guardian of our cells genes. This protein makes sure that healthy cells do not transform into cancer; not surprisingly, this protein is notably missing or defective in many pediatric brain cancers. Without p53, brain cancers in children also become resistant to treatment. Thus, restoring p53 function has great potential to improve treatment outcomes (Military Health Focus Area). SGT-53 is a new drug that allows for precise delivery of p53. It is a very small shell (nanoparticle) that carries the instructions for making p53. This shell is specially formulated to survive in the blood, get into the brain, and specifically target cancer cells. Inside the cancer cells, these instructions lead to production of p53, thus sensitizing cancer to treatment. By itself and with chemotherapy or radiation, SGT-53 has been shown to benefit mice with resistant brain cancers. Even more exciting, when given to a resistant brain cancer mouse model, SGT-53 seems to reactivate antitumor immunity and deactivate tumor-driven immune suppression, thus opening the door to increasing the brain cancer s susceptibility to the immune system. So far, in both children and adults, SGT-53 has been combined with chemotherapy, radiation therapy and immunotherapy, and has been both safe and exhibited exciting responses in otherwise resistant tumors. In the first two children with brain cancer treated with SGT-53 (in addition to chemotherapy and standard radiation), there were significant responses (greater than 50% tumor shrinkage in both). Encouragingly, SGT-53 also augments other forms of brain cancer treatment like radiation and immune checkpoint drugs. The combination of SGT-53, radiation, and immune checkpoint drugs has generated exciting tumor shrinkage in mouse models of resistant brain cancer. These treatments are often unable to control cancer on their own, but SGT-53 somehow encourages tumors to be more responsive. In this proposal, we are hoping to test this combination treatment in some children whose brain cancer has returned after previous therapy. It will include administration of SGT-53 for a week, followed by a brief (<5 days) radiation course in addition to administration of immune checkpoint drugs, followed by a repeat dose of SGT-53 and immune checkpoint drugs. We hope to verify that this three-part combination (SGT-53, radiation, immune checkpoint drugs) is safe and feasible. We also hope to closely monitor markers of immune response to see if this approach enhances the patient s defenses against the cancer antitumor immunity. In addition, to verify SGT-53 penetration across the blood-brain barrier and determine what changes SGT-53 makes to tumor cells, we will examine samples from . sic Although the trial is not designed to detect clinical responses, we will also be monitoring how patients tumors respond. Overall, we are hopeful that a positive trial will translate rapidly into a larger phase 2 trial in the near future. Military Relevance Focus Areas: The stress and intensive clinical care for a child with such a dire prognosis induces a considerable negative emotional impact for parents and families, especially if they are on military deployment and separated from their child. For these families in particular, the ability to offer their ill child cutting-edge, aggressive therapy provides si
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310987
Entities
People
- Eugene Hwang
Organizations
- United States Army