Pulmonary Macrophage Transplantation Therapy
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1 Pulmonary Macrophage Transplantation Therapy Rare Pediatric Respiratory Disease: Science Shapes Precision Care Conference Sanford Consortium for Regenerative Medicine La Jolla, CA July 6, 2017 Bruce Trapnell, M.D. Director, Translational Pulmonary Science Center Professor of Medicine and Pediatrics University of Cincinnati Medical Center
2 Outline Background Hereditary pulmonary alveolar proteinosis (hpap) Validated model Csf2rb-/- mice (KO) Pulmonary macrophage transplantation (PMT) therapy Overview of approach Therapeutic efficacy Cell localization, engraftment, differentiation Safety WT versus gene-corrected macrophages Nonclinical data status Clinical trial plan
3 Hereditary pulmonary alveolar proteinosis (hpap) Hereditary PAP is a rare disease characterized by accumulation of surfactant in alveolar macrophages and pulmonary alveoli causing restrictive lung impairment, and progressive hypoxemic respiratory failure Disease is caused by mutations in the genes encoding the GM CSF receptor α or β chains (CSF2RA, CSF2RB) GM CSF is required for alveolar surfactant clearance GM CSF regulates cholesterol clearance by macrophages constitutively and in reversible fashion Surfactant catabolism is not impaired PAP, but clearance is reduced secondary to cholesterol congestion
4 CSF2RA/B mutations known to cause hpap Chain (CSF2RA) NH 2 A17G + G196R G196R 920dupGC R217X Q170X Ex7 Ex7 8 Xp 0.4 Ex5&6 Xp 1.6, i(xq) Houston Xp 0.1 Signal Peptide Extra cellular 173 nt 192 nt 254 nt Transmembrane Intra cellular COOH Chain (CSF2RB) N S271L 631delC C Mouse GM CSF R β KO ( Ex7) Adapted from: Suzuki AJRCCM, 2010
5 hpap Pathology Reproduced in ips Cell-Derived Macrophages Blood hpap Normal Surfactant exposure Normal hpap hpap + gene Rx ips cells Before CSF2RA lentivirus S Gene corrected MΦs 0 hr after Surfactant Exposure Oil-red-O stain (neutral lipid) 24 hr after Suzuki AJRCCM. 189: ; 2014
6 Serum GM CSF Autoantibody ELISA Test GM CSF autoantibody (μg/ml serum) Optimal cutoff by ROC curve analysis Sensitivity & specificity = 100% based on ROC analysis Adapted from Uchida et al. J, Immunologic Methods. 402: 57 70; 2014
7 Serum GM CSF Concentration Routine ELISA performed using serum Used to screen for GM CSF receptor dysfunction Serum GM CSF (ng/ml) LLOQ 0.1 hpap Family members Healthy controls Suzuki, et al AJRCCM. 182: ; 2010.
8 GM CSF Signaling pstat5 Max Identifies Hereditary PAP 40 pstat5-max (MFI) NL apap spap hpap cpap
9 Current Therapy: Whole lung lavage Before After (5 days)
10 PMT therapy of hereditary PAP Gene-corrected macrophage L Defective macrophage due to CSF2RA mutations CSF2RB GM-CSF L CD34 O 2 Pulmonary alveolus CO 2 CD34 CSF2RA gene-correction vector Blood HSPC
11 Csf2rb / (KO) mice recapitulate human hpap a Human hpap CSF2RB S271L Murine hpap Csf2rb -/- (KO) h b c BAL turbidity (O.D. 600nm) WT KO d SP-D (mg/ml BAL) e WT KO WT KO *** f g WT KO *** *** WT KO *** *** GM-CSF (pg/ml BAL) M-CSF (pg/ml BAL) MCP-1 (pg/ml BAL) BAL GM-CSF (pg/ml) BAL turbidity (O.D. 600nm) PU.1 mrna (au) PPARγ mrna (au) ABCG1 mrna (au) *** *** i j *** *** *** *** WT KO WT KO WT KO nd *** 0 *** 0 *** WT KO k l Time (weeks) KO WT KO WT *** *** Suzuki Nature, 2014.
12 Preclinical evaluation of PMT therapy of hpap a Endotracheal administra on of macrophages into lungs Expansion WT HPSC s Macrophage HPSCs differen a on WT KO; gene corrected Csf2rb / (KO) mouse Suzuki Nature, 2014.
13 Lung histology 1 year after PMT WT KO KO + PMT SP-B PAS Suzuki. Nature, 2014.
14 PMT using WT or gene-corrected KO macrophages have similar therapeutic efficacy a GM-R-LV Mouse GM-R β Csf2rb IRES GFP-LV GFP CMV promoter cppt WPRE R enhancer RRE EF1α promoter U3Δ GFP U5 GFP b d Donor { LV vector { Recipient { GM CSF R β Ac n WT None KO KO GFP-LV KO KO GM-R-LV KO c d 4 e e g f * * BAL turbidity (OD 600 nm) SP D (mg/ml BAL) * * PMT cells { GFP-LV { GM-R-LV { WT KO + KO + 0 PMT cells { GFP-LV { GM-R-LV { WT KO KO PMT cells { GFP-LV { GM-R-LV { WT KO KO + + Suzuki Nature, 2014.
15 PMT corrects secondary polycythemia j Hemoglobin (mg/dl) Hemoglobin Hematocrit Erythropoietin * * PMT 0 { + WT KO k 60 l 600 Hematocrit (% rbc) * * Epo (pg/ml) * * PMT 0 { + PMT 0 { + WT KO WT KO Suzuki Nature, 2014.
16 PMT improves survival PMT Survival KO + PMT KO **** Age (days) Suzuki Nature, 2014.
17 Effect of cell dose on therapeutic efficacy of PMT Efficacy results summary (Pre clinical) Effector cell AMs, mature BMDMs, and progenitors have Rx efficacy Cell doses 5 x10e5 => similar efficacy 10e5 cells Rx effective at two months Cell dose/time to Rx effect = constant Strong cell survival advantage drives Rx Preclinical studies with clinical vector in patient cells completed/successful Trapnell, Pre Pre IND information package
18 c a MWM Transplanted macrophages remain in the lungs KO + PMT (1 month) KO + PMT (1 year) WT Lung Lys-M GFP+ Lung Blood BM Spleen Lung Blood BM Spleen - EGFP - Lys-M d b 2.0 Vector copy number Lung ND ND ND Blood BM Spleen Suzuki Nature, 2014.
19 c Transplanted macrophages localize to alveoli PMT: Lys M GPF Knock in BMDMs KO untreated KO + PMT Alveolar PMT-Derived Alveolar Interstitial d % PMT derived cells Interstitial Suzuki Nature, Endogenous 0 Alveolar Interstitial Localization
20 Transplanted macrophages engraft efficiently j k GM-CSF (pg/ml BAL fluid) Macrophage engraftment (% CD131+ BAL cells) l n * ns 0 WT KO +PMT BAL Turbidity (OD 600 nm) Cell number (x10 5 /mouse) 0 Suzuki Nature, Time after PMT (months)
21 GM CSF regulates alveolar macrophage population size via a reciprocal feedback mechanism M CSF Alveolar macrophage Survival Differentiation Population size GM CSF Blood Air M CSF Pulmonary GM CSF Lung Surfactant homeostasis Alveolar stability Oxygen uptake Suzuki Nature, 2014.
22 Importance of pulmonary GM CSF concentration GM-CSF Absent GM-CSF Increased Constitutively Unpublished
23 Transplanted macrophages adopt a normal phenotype Untreated controls Treated f BMDM WT (AM) KO (AM) KO + PMT (AM) % of Max CD11b Siglec F MCH class II SiglecF CD11c CD11b Suzuki Nature, Specific antibody Fluorescence Control antibody
24 Alveolar macrophage transcriptome 1 year after PMT a WT KO + PMT KO 0 1- Pearson correlation coefficient No change Suzuki Nature, 2014.
25 Results of preclinical safety studies PMT using WT or KO gene corrected macrophages into KO mice: No behavioral changes No cellular inflammation in the lungs No pro inflammatory cytokine increase in the lungs (TNFα, IL 1β, IL 6) No changes in baseline hematologic parameters Reduction in PAP biomarkers: M CSF, GM CSF, MCP 1 Doses of 5,000,000 cells/mouse were safe and well tolerated providing a 10 fold safety margin for cell dose Suzuki Nature, 2014.
26 Estimating the cell dose for PMT in humans Calculation method Human cell dose % AM # Alveolar number (relative) 0.03 x 10e9 0.5% Body weight (relative) 1.1 x 10e9 14% AM number (relative) 1.1 x 10e9 19% Alveolar surface area (relative) 4.4 x 10e9 78% AM number (absolute) 5.6 x 10e9 100% Based on values for corresponding mouse and human parameters 500,000 cells/mouse gives good/maximum efficacy at 1 year 100,000 cells/mouse gives detectable therapeutic efficacy at 2 months 4 x 10e6 cells/mouse was well tolerated and safe without adverse events Calculated from corresponding mouse and human parameter Calculate from the absolute human parameter
27 Translating PMT therapy to humans with hpap Dose No. Dose (40 kg human) Safety margin Delivery site 1 12 x 10e segment 2 24 x 10e segment x 10e6 8.8 All remaining segments Trapnell, Pre Pre IND information package
28 Conclusions Pulmonary GM CSF: Regulates alveolar macrophage population size, surfactant homeostasis, alveolar stability, and lung function GM CSF is a critical pulmonary hormone Pulmonary macrophage transplantation (preclinical): Myeloablation not required Safe and well tolerated High therapeutic efficacy Durable treatment effect (>1 year) Prolongs lifespan by 20% A strong survival advantage drives efficacy
29 Acknowledgements Translational Pulmonary Science Center, Cincinnati, OH, USA Takuji Suzuki Paritha Arumugam Takura Sakagami Claudia Chalk Antony Sallese Brenna Carey Bruce Trapnell Experimental Hematology, Cincinnati, OH USA Punam Malik Carolyn Lutzko Pulmonary Medicine, Cincinnati, OH, USA Robert Wood (Harvard Medical School, Cambridge, MA, USA) Cole Trapnell Hannover Medical School, Hannover, Germany Nico Lachmann Thomas Moritz Funding (PAP Research Program) NIH UL1 RR NIH R01 HL NIH R01 HL NIH U54 HL12762 (NIH R21 HL106134) (NIH R01 HL71823) (NIH U54 RR019498)
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