Abstract A081: Patient-derived xenograft models from hematological malignancies for preclinical drug development and biomarker research

Abstract

Abstract Background: Acute leukemias and lymphomas encompass a diverse group of hematologic malignancies, posing significant challenges in clinical practice. They often exhibit resistance to standard-of-care (SoC) treatments and have a high recurrence rate. Recent advancements in molecular profiling have identified potential drivers for various leukemia and lymphoma subtypes, offering new therapeutic targets. However, the validation of these targets and the development of drugs rely heavily on preclinical models that faithfully represent the different clinical subtypes. These models play a crucial role in refining target selection and facilitating drug development projects. Methods: AML- and ALL-PDX were derived from bone marrow aspirates or peripheral blood samples, from primary or relapsed acute leukemia patients. Purified cells were transplanted either intravenously (i.v.) and/or subcutaneously (s.c.) into immunodeficient mice. Some mice developed a systemic AML, which was monitored by flow cytometric analysis of blood samples. Non-Hodgkin (NHL) - or Hodgkin lymphoma (HL)-PDX were derived from peripheral blood, lymph node extirpations or core needle biopsies, and were usually transplanted subcutaneously into immunodeficient mice. Results: More than 45 PDX models from AML, ALL, NHL and HL have been successfully established and characterized. Highly individual response rates to SoC and investigational drugs were observed and correlated with mutation and gene expression data. An individual Human Leucocyte Antigen (HLA) profile of each PDX was determined by RNA-seq and a comprehensive HLA matching analysis of the models and peripheral blood mononuclear cell (PBMC) donors was performed to enable personalized, preclinical immuno-oncology studies. Conclusions: Our extensively characterized PDX models derived from hematologic malignancies serve as valuable tools for evaluating novel targeted and immunological therapies. These models provide an exceptional platform for identifying and validating new targets, as well as preclinical screening of compounds and combinations for translational research projects in this field. Citation Format: Antje Siegert, Bernadette Brzezicha, Stephan Fuhrmann, Martin Janz, Clemens Schmitt, Ulrich Keller, Christian Rupp, Wolfgang Walther, Jens Hoffmann. Patient-derived xenograft models from hematological malignancies for preclinical drug development and biomarker research [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A081.