IMMU-41. IMMUNOLOGICAL TARGETING OF SLOW-CYCLING CELLS TO PREVENT RECURRENCE IN GBM

Abstract

Abstract Glioblastoma (GBM) is the most common primary malignancy of the central nervous system (CNS) and is typically fatal due to recurrence despite aggressive treatment. Targeting residual cells after surgical tumor removal is challenging due to the infiltrative nature of GBM. It is crucial to develop effective adjuvant therapies that can combat the drivers of disease recurrence. Traditional anticancer treatments tend to eliminate rapidly dividing cells while sparing dormant or infrequently dividing populations. Numerous studies have identified slow-cycling cells (SCCs) in various cancers, including high-grade glioma, which are resistant to therapies. Our laboratory has discovered SCCs in high-grade glioma, which are highly infiltrative and treatment-resistant cells responsible for driving recurrence. It is imperative to develop an effective strategy to specifically eliminate this cell population in order to reduce recurrence and improve survival rates. Importantly, these cells have a defined cellular niche that contains potentially immunogenic neoantigens, making them suitable targets for immune-based therapies. Our primary objective is to utilize SCC antigens in the form of RNA or peptides to stimulate the immune system and enable it to identify and target treatment-resistant clones. By focusing on these crucial drivers of recurrence, our aim is to achieve strong and effective tumor control. Our research findings indicate that our approach effectively primes T cells to identify and target treatment-resistant cells in glioma. Our results demonstrated that T cells specific to slow-cycling cells (SCC-T cells) showed greater activation when exposed to treatment-resistant tumor cells, as evidenced by increased differentiation of CD8 cells and enhanced development of effector and memory cells. Furthermore, SCC-T cells exhibited the highest level of anti-tumor activity, resulting in a significant reduction in tumor cell proliferation and an increase in apoptosis. Taken together, these results highlight the effectiveness and superiority of our SCC-based immunotherapy platform in targeting treatment-resistant glioblastoma cells.