Managing an Organ - New Therapies

Transcription

1 Managing an Organ - New Therapies Marcelo Cypel MD MSc Canada Research Chair in Lung Transplantation Surgical Director, ECLS program UHN Assistant Professor of Surgery Division of Thoracic Surgery University of Toronto

2 DISCLOSURE Vitrolife, XVIVO Perfusion Research support and clinical trial Co-founder and Medical Officer Perfusix Canada and United States Co-founder XOR Toronto Labs

3 First Successful Lung Transplantation in the World Toronto General Hospital1983

4 First Lung Tx First Double Lung Tx

5 Indications(TGH) N=1500 Cystic Fibrosis 22% Eisenmenger's 3% PAH 5% BAC 1% COPD/ Emphysema 33% ILD/IPF 31% Re-Tx 3% Other 3% 5

6 Major Obstacle for Lung Transplantation Success Absence of sufficient organs to meet the growing demand! Up to 30% patients die on wait lists Larger number of patients are not even listed

7 Low Utilization Rates BDD=17% DCD=2%

8 Munshi L, Keshavjee S, Cypel M. The Lancet RM Volume 1, Issue 4, Pages , June 2013

9 Clinical Problem - PGD

10 Reduction of cell metabolism by 95%

11 Normothermic Preservation Time to accurately assess, diagnose (improve utilization) Option to treat, recover, repair (targeted) Opportunity to reassess confirm results of treatment

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13 Lindbergh, Science, 1935

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15 Couves, CM

16 TORONTO EX VIVO LUNG PERFUSION (EVLP) SYSTEM Perfusion : 40% CO, LAP 5mmHg, PAP 10-12mmHg Ventilation: 7cc/kg, 7BPM, PEEP 5, FiO 2 = 21% Cypel et al. J Heart Lung Transplant 2008; 27(12):

17 Toronto Sky Dome Toronto XVIVO TM System

18 DEVELOPMENT OF A STABLE AND RELIABLE EX VIVO LUNG PERFUSION TECHNIQUE Cypel/Keshavjee. Technique for Prolonged Normothermic Ex Vivo Lung Perfusion. J Heart Lung Transplant 2008;27(12):

19 NORMOTHERMIC EX VIVO PERFUSION INTERRUPTS COLD ISCHEMIC INJURY (24h) Cypel/Keshavjee. Normothermic ex vivo perfusion prevents lung injury compared to extended cold preservation for transplantation. Am J Transplant Oct;9(10): CSP EVLP

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21 VIDEO

22 22 NEJM, April 14 th 2011, vol. 364, no. 15, pp

23 Study Logistics Donor Lungs Referred for EVLP Cold Ischemic Time 1 (transportation) EVLP for 4-6h P/F>400mmHg, stable or improved PawP, PVR, Compliance, X-ray Cold Ischemic Time 2 Transplantation

24 Bronchoscopy

25 Lung Xray

26 Stable or Improved Ex vivo Function

27 NEJM, April 14 th 2011 Early outcomes were similar in the 2 groups

28 Cypel et al. Experience with the first 50 ex vivo lung perfusions in clinical lung transplantation. JCTVS September 2012

29 Percent survival Survival controls (n=253) EVLP (n=50) p= Years after LTx Cypel et al. Experience with the first 50 ex vivo lung perfusions in clinical lung transplantation. 0 JCTVS 365September

30 Percent survival Survival p=0.71 controls (n=253) EVLP BDD (n=28) EVLP DCD (n=22) Years after LTx

31 EVLP Experience in Toronto Assessed (n=105) Transplants (n=84) Transplants (n=21) Utilization Rate of EVLP Lungs 84/105 = 80%

32 '08 '09 '10 '11 '12 '13 No of Tx / yr EVLP Lung Tx Year

33 Current State of EVLP > 300 cases done North America and Europe 3 clinical trials (1 US and 2 Europe) XVIVO, Transmedics, Vivoline

34 Engineering Superior Organs

35 Ex vivo treatment opportunities Donor lung injuries 1- Pulmonary Edema 2- Brain death associated inflammation 3- Infection, Pneumonia 4- Aspiration 5- Pulmonary emboli 6- Ischemia-reperfusion injury 7- Immunologic preparation

36 Advantages of ex vivo treatment Increased time for interventions Avoid systemic side effects Treatment is specific to the organ Prolonged half-life of drugs in perfusate Absence of systemic inflammatory milieu Opportunity for post-treatment re-assessment

37 Resolution of pulmonary edema during EVLP Donor P/F 230 1h EVLP Recipient P/F 420 3h EVLP

38 Infection Large proportion of rejected human lungs EVLP is ideal Super high doses of antibiotics can be administered without systemic effects Prolonged half-life. Start with treatment of early infections or lung contralateral to established pneumonia Prolonged perfusion (>12h) might be required

39 Repairing Human Lungs with Presumed Infection 6 lungs rejected for suspicion of infection 12h normothermic EVLP with high doses of antibiotics 600 Pneumonia - Mean Delta po 2 (FiO 2 1)

40 10 6 CFU/L 10 6 CFU/L 10 6 CFU/L 10 6 CFU/L 10 6 CFU/L 10 6 CFU/L Ex Vivo Treatment of Infection Ps Aeruginosa (n= 4) S Aureus (n= 3) St Maltophilia (n= 3) control 0h 6h 12h h 6h 12h h 6h 12h Trichosporon (n= 3) E Coli (n= 2) Enterobacter (n= 1) h 6h 12h h 6h 12h control 0h 6h 12h 40

41 Personalized Medicine for the Organ Clinical Case: Diagnosing and Treating a Specific Problem 41

42 Surgical Extraction of Large Clots of Varying Age in Donor Lung PA

43 EVLP Assessment confirms the in vivo findings On initiation of EVLP: abnormal PA pressures even with low flows Persistent hemodynamic impairment in the ex vivo organ Apply similar diagnosis / treatment as in vivo treatment of massive PE ALTEPLASE 20 mg (reduced clearance)

44 Significant improvement of Pulmonary Hemodynamics after treatment Alteplase diagnosis treatment Response monitoring

45 D-dimer and Evidence of Thrombolysis Ex vivo treated lung with massive PE 11-fold increase

46 Pathology: Ex vivo lung biopsy, Quick Section pathologic Examination No evidence of chronic vascular abnormalities

47 Change from Baseline (mmhg) (dynes.sec.cm -5 ) Functional Repair of Human Donor Lungs by Ex Vivo IL-10 Gene Therapy Delivery of IL-10 by EVLP Ad Gene Therapy to injured human donor lungs resulted in improved lung function PaO 2 /FiO * PVR * EVLP/AdIL-10 EVLP M Cypel, M Liu, M Rubacha, J C Yeung, S Hirayama, M Anraku, M Sato, J Medin, BL Davidson, M de Perrot, TK Waddell, A S Slutsky, S Keshavjee. Sci Trans. Med 1:4ra9; 2009.

48 Recovery of alveolar epithelial cell tight junctions (ZO-1) after AdhIL-10 gene therapy in Human Lungs. Cypel/Keshavjee et al. Science Translational Medicine Oct 28, 2009.

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51 The Future of Transplantation The Organ Repair Center Lung Heart Liver Kidney

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54 Exterior Rendering Spring Street Façade/Orange

55 Donor Management Organ Procurement Cold Preservation Ex vivo Evaluation Ex vivo Organ-Specific Injury Repair Transplantation

56 Thank you!