Mentor Name: Iannis Aifantis

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, and while targeted immunotherapies have significantly improved outcomes, resistance remains a major clinical challenge. Inotuzumab ozogamicin, a CD22-targeting antibody-drug conjugate (ADC), has emerged as an important treatment option for relapsed or refractory B-ALL. However, antigenic escape through CD22 downregulation or functional loss can lead to resistance, limiting its efficacy. Previously, our research focused on CD19 antigenic escape mechanisms in B-ALL and their implications for CAR T-cell therapy and blinatumomab resistance. Building on this knowledge, we have extended our investigations to the biology of CD22 to understand how its regulation impacts inotuzumab response. We have conducted CRISPR-based screens to identify genetic regulators that upregulate CD22 expression. Now, we aim to perform a functional CRISPR screen in the presence of inotuzumab to identify mechanisms driving resistance under selective pressure. By integrating genetic screening with functional validation studies, we seek to uncover key regulators that influence CD22 expression and inotuzumab sensitivity. The findings from this study could have significant clinical implications, providing new insights into resistance mechanisms and informing strategies to enhance the durability of CD22-targeted therapies. Ultimately, this research aims to contribute to the development of more effective treatment approaches for pediatric B-ALL patients who currently face poor outcomes due to therapy resistance.