IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies
Pablo Domizi, Jolanda Sarno, Astraea Jager, Milton Merchant, Kaithlen Zen B Pacheco, Sean A. Yamada‐Hunter, Maria Caterina Rotiroti, Yuxuan Liu, Reema Baskar, Warren D. Reynolds, Brian J. Sworder, Bita Sahaf, Sean C. Bendall, Charles G. Mullighan, Ash A. Alizadeh, Allison Barz Leahy, Regina M. Myers, Bonnie Yates, Hao‐Wei Wang, Nirali N. Shah, Robbie G. Majzner, Crystal L. Mackall, Stephan A. Grupp, David M. Barrett, Elena Sotillo, Kara L. Davis
Abstract
Abstract Antigen escape relapse is a major challenge in targeted immunotherapies, including CD19- and CD22-directed chimeric antigen receptor (CAR) T-cell for B-cell acute lymphoblastic leukemia (B-ALL). To identify tumor-intrinsic factors driving antigen loss, we perform single-cell analyses on 61 B-ALL patient samples treated with CAR T cells. Here we show that low levels of IKAROS in pro-B-like B-ALL cells before CAR T treatment correlate with antigen escape. IKAROS low B-ALL cells undergo epigenetic and transcriptional changes that diminish B-cell identity, making them resemble progenitor cells. This shift leads to reduced CD19 and CD22 surface expression. We demonstrate that CD19 and CD22 expression is IKAROS dose-dependent and reversible. Furthermore, IKAROS low cells exhibit higher resistance to CD19- and CD22-targeted therapies. These findings establish a role for IKAROS as a regulator of antigens targeted by widely used immunotherapies and in the risk of antigen escape relapse, identifying it as a potential prognostic target.