Pharmacogenomic Determinants of Inotuzumab-ozogamicin Resistance in B-cell Acute Lymphoblastic Leukemia

• Applicant: Dr. Carolin Escherich
• Subject Area: Hematology, Oncology
• Term: from 2023 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 519605261

Studies on the treatment of B-cell acute lymphoblastic leukemia (B-ALL) greatly improved the prognosis of this cancer. However, treatment of high-risk leukemia or at relapse remains challenging, necessitating novel treatment options to further improve patient outcomes and survival. Inotuzumab-ozogamicin is a novel antibody-drug conjugate that is gaining importance in the treatment of high-risk B-ALL. The antibody targets CD22, a cell-surface protein, that is specifically expressed by B-lineage lymphoid cells. The antibody is linked to the tumor antibiotic Calicheamicin. Upon CD22 binding, the antibody-drug conjugate is internalized and Calicheamicin is released from the complex. Calicheamicin enters the nucleus and potently induces DNA double-strand breaks, subsequently leading to apoptosis of CD22-positive cells. Clinical trials in children and adults with relapse or refractory B-ALL showed great response to Inotuzumab-ozogamicin treatment. However, there are also a significant number of patients, that respond inadequately to this treatment or relapse. To identify genomic determinants related to Inotuzumab-ozogamicin treatment response, we performed a genome-scale CRISPR/Cas9 knockout screen, using the B-cell precursor cell line Nalm6. In this approach, we identified loss of CD22 expression and loss of DNA Nucleotidylexotransferase (DNTT) expression to be most significantly related to Inotuzumab-ozogamicin resistance. Loss of CD22 expression, as the target of Inotuzumab-ozogamicin, has been previously reported in treatment failure. In contrast, little is known about DNTT expression in the context of chemotherapeutic drug resistance. Preliminary results from in vitro experiments confirmed, that loss of DNTT expression significantly improves cell survival during Inotuzumab-ozogamicin treatment. The correlation of B-ALL patient genomic data and ex vivo Inotuzumab-ozogamicin sensitivity further supports the contribution of DNTT expression to Inotuzumab-ozogamicin resistance. In this study, we aim to (1) characterize the molecular mechanism by which DNTT mediates Inotuzumab-ozogamicin resistance, and (2) evaluate the association of DNTT expression and Inotuzumab-ozogamicin response in B-ALL patients to determine its utility as a predictive biomarker.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Dr. Jun Yang