Abstract 4210: Patient-derived models of human acute myeloid and lymphoid leukemia in immunocompromised mice for preclinical drug development

Abstract

Abstract The generation of functional and reproducible in vivo models is a prerequisite for a better understanding of hematological malignancies and for the development of improved therapeutic strategies. Here, we report the establishment of transplantable PDX models of acute myeloid and lymphoid leukemia (AML, ALL) growing subcutaneously (s.c.) as well as in a disseminated fashion in immunocompromised mice. Bone marrow (BM) and peripheral blood (PB) cells from 25 AML/ALL patients were injected intratibially into NSG or NOG mice (n = 1-9/patient) and in later passages also s.c. in nude mice (n = 1-3/model). Tumor growth was monitored via determination of overall survival, flow cytometry (verification of patient-derived leukemic clones by hCD34, hCD33, hCD38, hHLA-ABC, hCD3, hCD45, mCD45), and, where applicable, by caliper measurement. Engraftment is defined as ≥5% hCD45+ cells in the BM and/or ≥1% hCD45+ cells in PB. Transplantable models (higher or equal passage 2) were tested with the respective standard of care drugs (SoC) mainly Cytarabine and Dexamethasone. Bone marrow engraftment in passage 1 was observed for 11 out of 25 leukemia models. Four of them could be established as disseminated models in serial passage. No engraftment was detected for nine models during the observation period of at least 95 days while observation for five models is still ongoing. The four established models were further characterized by fluorescence-in-situ-hybridization (FISH) to confirm patient origin. Treatment of mice bearing the models with the SoC drugs cytarabine and dexamethasone significantly prolonged overall survival. Antitumoral activity was consistent with clinical response of the donor patient. One T-ALL and two AMLs were additionally successfully propagated following s.c. injection in nude mice. They showed stable growth behavior and displayed a similar chemo-sensitivity pattern as their disseminated growing counterparts. In conclusion, we have established a panel of transplantable PDX models of ALL and AML displaying stable and reproducible growth patterns suitable for in vivo efficacy studies. Our results confirm that PDX models of hematological malignancies replicate important clinical characteristics of the disease and are valuable tools for preclinical drug testing. Citation Format: Eva Oswald, Kerstin Klingner, Benedikt Hammerich, Gabriele Greve, Dorothee Lenhard, Milena Pantic, Heinz-Herbert Fiebig, Michael Luebbert, Julia B. Schüler. Patient-derived models of human acute myeloid and lymphoid leukemia in immunocompromised mice for preclinical drug development. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4210. doi:10.1158/1538-7445.AM2015-4210