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AACR April, 2016 – Humanized Mouse Models for Evaluation Of Humanized Mouse Models for Evaluation of Cancer Therapies 5196 O. Duchamp1, F. Bichat1, C. Mignard1, F. Ghiringhelli2, J.-F. Mirjolet1 1 2 Oncodesign, Dijon, Center Georges Francois Leclerc, Dijon (FRANCE) For more information: [email protected] Generation of human immune system reconstituted mice hHSCs reconstituted mice hPBMCs reconstituted NOG mice Mice with a humanized immune system, so called “humanized” mouse models, have PDX tumor growth is not Tumor growth modifies the composition of central lymphoïd and IV B cell lymphoma SC plasma cell lymphoma affected by humanization myeloïd cells in blood of humanized BRGS mice (Flow cytometry) been established to study the complex interaction of the human immune system during 2500,00 in BRGS mice 100 ) human disorders. In case of cancer research, the in-vivo model ideally should recapitulate 3 the biological characteristics of the human tumor and of the related tumor CD3 (Blood) CD4-FoxP3 (Blood) 2000,00 100 80 25 microenvironment in patient such as immune system. 90 1500,00 80 20 19,4 60 Vehicle L U N -N IC -0 0 8 4 70 17,6 1000,00 Control 1 0 0 0 60 15 + Bispecific Survival (%) Human immune system is reconstituted in immunodeficient mice using either human ) 21 – 62% hCD45 cells 50 48,6 40 3 (in total leukocytes) 11,0 m 8 0 0 40 10 500,00 FoxP3 (% of hCD4) (% of FoxP3 m PBMCs or hematopoietic stem cells (HSCs). Humanized mice bearing human target tumor - ( 30 Control Median Tumor Volume (mm Volume Tumor Median e 6 0 0 5 20 m 20 Bispecific cells constitute relevant models for evaluation of cancer therapeutics such as bispecific u 0,00 l 13,2 human human (% of hCD45) CD3 10 10,4 o 0 5 10 15 20 25 30 35 40 v 4 0 0 0 antibodies, immune cell targeting antibodies. r 0 0 o Time (Days) human human CD4 0 1 2 3 0 10 20 30 40 50 m 2 0 0 0 1 2 3 u T Time (days) 0 IV/Intracardiac 0 2 0 4 0 6 0 Humanization did not modify tumor IP/IV HSCs PBMCs T im e (d a y s ) progression CD20 (Blood) Tumor induced: BM Total hCD45 BCL cells 80 Death of mice is related to tumor development 72,7 Murine immune 70 • Increase in Treg I system depletion 60 59,1 Efficacy of the compound 50 • Decrease in T/B ratio IM -O V A -5 0 3 47,5 N 40 Control . Increased survival and tumor regression 1 0 0 0 SCID + 30 ) 20 – 80% hCD45 cells NOD SCID 3 . Spleen: no remaining B cells 20 m (in total leukocytes) NSG/NOG… R 8 0 0 m T ( 10 . Bone marrow: significant decrease in BCL e 6 0 0 human CD20 (% of hCD45) (% ofhuman CD20 m 0 u l 0 1 2 3 cells o E v 4 0 0 R r o hPBMC humanized and tumor bearing mouse Treated m 2 0 0 u O S T Model of interest for further evaluation of compounds targeting model are of interest to evaluate T cell POC studies with hPBMCs reconstituted mice 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 Tregs or interfering with CD8/CD4 populations (ipilimumab, recruiting compounds such as bispecific antibody . Injection of human PBMC in irradiated NOG mice T im e (d a y s ) D U nivolumab…) or to evaluate engineered immune cell based . IV injection of B-cell lymphoma or SC injection of plasma cell myeloma therapy such as CAR-T cells. U . Tumor volume monitoring with caliper for SC tumor, mice termination when hind leg L paralysis for IV tumor T Spleen : non-tumor bearing mice vs tumor bearing mice C . Quantification of immune cell populations and tumor cells in blood bone marrow Tumor infiltration by human immune cells Conclusions and spleen samples using flow cytometry analysis (IV tumor model) S Healthy Tumor-bearing T ID36 ID20 ID11 ID37 I Treg identified within the tumor (n=2) POC studies with hHSCs reconstituted mice T/B= 3.0 T/B= 1.3 T/B= 0.1 O Humanization of immune system of mice . Injection of human HSC in BRGS mice T/B =0.6 N . SC xenograft of lung and ovarian PDX tumor samples with either hPBMCs of hHSCs permits the . Tumor volume monitoring with caliper growth of human tumors either SC vs IV xenografted, . Mice termination for collection of blood, spleen, bone marrow and tumor hCD20 . Quantification of immune cell populations using flow cytometry and hCD3 immunohistochemistry analysis Lymphoid and myeloid cells, in particular Treg, are detected in blood and tumors from Immune system reconstituted mice 10.1 12.6 18.2 17.2 humanized mice, A large panel of humanized mouse models to address 13% specific immune cancer cell questions Tumor Lymphoid cells & Myeloid cells h T - c e lls Humanized mouse models constitute ( 2 4 5 m ic e ) (Flow cytometry analysis) 48% preclinical tools for studying immunologic h P B M C s • T cells: ~55% Oncodesign has a large experience with immune system Foxp3 h H S C s process and evaluating immunomodulating 33% ( 8 9 6 m ic e ) reconstituted mice xenografted with solid tumors hCD4 • B cells: ~4% ( 6 0 5 m ic e ) agents in complement of our syngeneic mouse (BT474, FaDu, HCT-116, LoVo, PDX…) as well • NK cells: ~6% ( 1 1 5 m ic e ) model platform. h N K s as hematological tumors (Daudi, Karpas-299, Ramos…) Representative flow cytometry pictures showing human T & B cells population (top panel), • Monocytes: ~3% 6% Treg population (bottom) in healthy (left) and tumor bearing mice (right). • Other myeloid cells: ~5% This work was partly supported by a grant from and the French Government .
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