Combinatorial Targeting of High-Risk Neuroblastoma by Localized FLASH Proton Therapy and Systemic Immunotherapy
Abstract
Neuroblastoma (NB) is a deadly nervous system cancer in children age 5 or younger. About 50% of patients develop high-risk NB with poor outcome. Nearly half of the patients have the cancer spread to other parts of the body, making it very difficult to treat. Current treatments, including surgery, drugs, immunotherapy, and radiation, usually cause long-term side effects and still end in relapse, with tumors redeveloping. Thus, there is an urgent need to create new treatment approaches that are both better at destroying the tumors and less harmful to the body. Radiation therapy (RT) can kill cancer cells and activate the immune system, but these benefits cannot be maximized due to collateral damage to surrounding healthy tissues. Proton RT is one of the most precise and advanced forms of RT used in NB treatment and can address the toxicity issue to a certain extent. The Proton Therapy Center at Cincinnati Children’s Hospital is currently the only center in the nation that includes a dedicated gantry for proton irradiation research in animal models. Recently, radiation delivered at extremely fast speed (completed in less than a second, compared with several minutes conventionally) known as FLASH, promises to be a groundbreaking strategy for killing cancer cells with minimal harm to surrounding healthy tissue. However, this strategy has not been tested in children with high-risk NB. To leverage our unique proton research facility, we will investigate the impact of innovative FLASH proton treatment on growth and progression of high-risk NB in preclinical mouse models, including mice engrafted with patient-derived NB. The tumors in these mice are very similar to those seen in high-risk NB patients. We therefore can use these mice to learn about NB biology in response to FLASH proton therapy. Another major cause of death for patients with high-risk NB is that cancer often spread to other parts of the body. Although immunotherapy that help make cancer cells visible to immune cells, which act like police cells in the body, has shown success in adult cancer patients, immunotherapy as a monotherapy is not effective for children with high-risk NB because pediatric cancers use different evasion strategies to hide themselves from the immune system. Local radiation to tumors can activate the immune system in the body, allowing immune T cells to detect and kill metastatic tumors that have not been irradiated. This is a rare phenomenon called the abscopal effect. Combining radiation and immunotherapy, including immune checkpoint inhibitors should be a powerful strategy to take advantage of abscopal effect for elimination of local and metastatic cancers. We hereby propose an innovative NB treatment strategy combining the benefits of FLASH proton radiation to local tumors and systemic immunotherapy for distant, metastatic NB elimination. We will test this novel combination treatment in mouse models bearing high-risk NB. (Section II.A.2: Mission readiness-gaps in treatment that may impact the mission readiness and the health of the beneficiaries of military members and the general public). Cancer behaviors, including how a tumor grows, spreads, and resists being killed by therapy critically depend on how tumor cells talk among themselves and to the surrounding cells through a signal sending-receiving relationship. To understand what signal is exchanged between individual cells within a tumor, we use single-cell transcriptomics and epigenomics that enable us to detect global gene expression patterns of individual cells and what gene networks control these patterns at very high resolution. Single-cell data can tell us what cell populations are within a tumor and how they talk to one another to respond to therapy. One way tumor cells become more powerful is to escape from surveillance by immune T cells. We can develop drugs to make cancer cells more visible to the immune system. This will open new opportunities fo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310453
Entities
People
- Lai Man Wu
Organizations
- United States Army