Glioblastoma stem cell vaccine for the prevention and control of glioblastoma

Project Summary/Abstract Glioblastoma (GBM) is an aggressive and incurable primary brain tumor under the current standard of care. Even the recently revolutionized immune checkpoint blockade immunotherapy has been found ineffective in GBM patients, highlighting an urgent need for effective treatments. Cancer vaccines, such as peptide- or dendritic cellbased vaccines, have been tested in GBM; their overall success remains limited and has produced variable results. This underscores the need for consistent and effective novel approaches to address this lethal disease. Glioblastoma stem-like cells (GSCs), a subpopulation of GBM tumor cells, are critical therapeutic targets because they drive tumor initiation, progression, maintenance, treatment resistance, and tumor recurrence. To develop GSCtargeted GBM therapeutics, we have established unique GSC-based murine GBM models and a novel GSC-based anticancer vaccine. Our preliminary data indicate that the GSC vaccine provides 100% protection against GBM, compared to only 20% protection achieved with tumor cell-derived vaccines, with T lymphocytes (such as CD4+ T cells) playing a pivotal role in the immune response induced by the GSC vaccine. This research project aims to further delve deeper into testing the potential of this GSC vaccine in eradicating GBM. To achieve our study objectives, we have proposed two specific Aims: In Aim #1, we will assess the vaccine’s ability to induce immunogenic cell death, homologous and heterologous protection against GBM, and immunological response against GSCs and GBM tumor cells. In Aim #2, we will evaluate the therapeutic efficacy of the GSC vaccine against established orthotopic GBM in both homologous and heterologous scenarios, focusing on durable therapeutic efficacy. This innovative approach represents the first attempt to use live-irradiated GSCs as a potent vaccine for GBM, exploring both prevention and treatment paradigms, as well as homologous and heterologous protection. If successful, this project has the potential to revolutionize GBM treatment by introducing live-irradiated GSCs as a novel therapeutic approach. Additionally, this strategy could be adapted to offer personalized treatment options for GBM patients. Our research team provides a solid foundation for success, comprising multiple investigators with complementary expertise in GSCs and preclinical GBM models, clinical immunotherapy, cancer immunology, neuroscience, radiation oncology, mentoring students, and career guidance. Furthermore, this project will have profound and far-reaching implications for our graduate and undergraduate students, including: (i) the development of a neuro-oncology GBM research program at North Carolina Agricultural and Technical State University (NC A&T), a distinguished institution and a research intensive university of the University of North Carolina (UNC) system, (ii) comprehensive training opportunities for NC A&T students in advanced topics such as cancer stem cells, cancer vaccines, animal models, and tumor immunology, and (iii) the strategic mentorship of NC A&T’s graduate and undergraduate students in translational research, particularly in understanding the clinical aspects of this project.