Abstract 1150: Acute myeloid leukemia human/mouse co-clinical trial feasibility study optimized in human transgenic IL-3/GMCSF NOD/Shi-scid-IL2rγnull mice
Authors: Goodwin Neal C. , Albert Daniel H. , Davies Angela M. , Rowe Jenny , Feuer Gerold , Boyiadzis Michael , Dorritie Kathleen A. , Mancini Maria , Gandour-Edwards Regina , Kati Warren M. , McKee Mark D. , McDaniel Keith F. , Frost David J. 
Published: August 2018

Acute myeloid leukemia (AML) co-clinical modeling has been optimized with peripheral blood mononuclear cells (PBMCs) collected from low volume (14 mL) patient samples to establish an algorithm for efficiently co-clinically modeling AML patients. Methods: PBMCs were ficoll gradient purified and viably cryopreserved. Intrahepatic (i.h.) inoculation of AML PBMCs in neonate NOD/Shi-scid-IL2rγnull (NOG) mice and intravenous (i.v.) inoculation in both juvenile NOG mice and juvenile human transgenic IL-3/GMCSF NOD/Shi-scid-IL2rγnull mice (NOG-EXL) were evaluated. Bone marrow (BM) aspirates, splenocytes and PBMCs from mice were evaluated by fluorescence-activated cell sorting (FACS) at 12 weeks post AML inoculation for engraftment as determined by % ratio of human CD33+ cells to total CD45+ cells (human + murine cells). Humerus bones from inoculated animals were also evaluated by human CD33 immunohistochemistry (IHC). Results: Cells from 2/6 AML patient samples (CTG-2224 and CTG-2357) successfully engrafted into neonate mice. Animals were dosed with vehicle, cytarabine, ABBV-075 (clinical trial-staged BET family bromodomain (BD) inhibitor), or ABBV-744 (a preclinical BDII selective inhibitor) and evaluated for tumor burden six weeks post drug treatment initiation. ABBV-075 and ABBV-744 treated animals had lower tumor burden in the CTG-2224 model, 17% (p&lt;0.05) and 4% (p&lt;0.01); respectively. Similar trends, albeit at lower engraftment (10%), were observed for both models in spleen and blood compartments. In an effort to improve engraftment efficiency NOG-EXL mice were evaluated as hosts for engraftment with a patient PBMC sample (CTG-2357) and compared with juvenile NOG mice. Efficiency in the number of mice engrafted (8/8 vs. 3/7) and the extent of BM engraftment (51% vs. 14%) following a 0.5 X 106 PBMC inoculation was improved with the NOG-EXL mice. Furthermore, a patient inoculum (CTG-2241) that had previously shown no engraftment in juvenile NOG mice exhibited a 92% take rate with 93% BM tumor burden in NOG-EXL mice. Discussion: Prior advances in AML modeling show engraftment in IL2rγnul mouse models including i.h. and i.v. inoculation of BM clinical isolates in neonate NSG mice, i.v. inoculation of leukapheresis clinical isolates in juvenile NSG and NSG-SGM3 mice, and i.v. inoculation of BM aspirates in MISTRG mice. Each approach has limitations in terms of tedious neonate mice husbandry, ease of clinical sample collection with respect to clinical patient compliance, and mouse strain availability. Here we examined the feasibility of efficiently engrafting AML regardless of mutation or clinical stage from 14 ml PBMC samples. Results showed that i.v. inoculation of AML clinical samples in juvenile NOG-EXL mice was advantageous. This research is prerequisite for conducting translational co-clinical in vivo pharmacology studies for ABBV-075.

Citation Format: Neal C. Goodwin, Daniel H. Albert, Angela M. Davies, Jenny Rowe, Gerold Feuer, Michael Boyiadzis, Kathleen A. Dorritie, Maria Mancini, Regina Gandour-Edwards, Warren M. Kati, Mark D. McKee, Keith F. McDaniel, David J. Frost. Acute myeloid leukemia human/mouse co-clinical trial feasibility study optimized in human transgenic IL-3/GMCSF NOD/Shi-scid-IL2rγnull mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1150.