In the last five years, the FDA and EMA approval of four CD19-targeting chimeric antigen receptor T cell (CAR-T) products have revolutionized the treatment of patients with relapsed and/or refractory B cell malignancies. However, about 50% of patients treated with CD19-targeting CAR-T (CAR19) therapy don’t achieve durable disease control due to a lack of functional CAR-T persistence or tumor resistance. Resistance mechanisms are multifactorial (tumor intrinsic, immunosuppressive microenvironment, and CAR T cell dysfunction), and CD19 escape variants substantially contribute to it. Therefore, we hypothesize that CD19 escape variants must be present at a critical threshold in a heterogeneous tumor population to grow out under CAR19 treatment. We will employ a CRISPR-based editor tiling screen as an unbiased approach to discover CD19 escape variants to CAR19 therapy. We have designed a CD19 tiling screen library of 11,500 potential sgRNAs (targeting protein-coding sequences, promoters, enhancers, introns, and UTRs) to recruit cytokine and adenine base editors. Next, to verify the functional consequences of identified CD19 escape variants, we will perform confirmatory in vitro and in vivo assays. Our findings hold the potential for future clinical translation to predict patients' disease relapse and to guide the selection and design of personalized CAR-T products.