the future is immunotherapy cccf 2014.ppt · my talk for today • frame the ... (clp/mscs)...
TRANSCRIPT
The Future is Immunotherapy
Lauralyn McIntyre MD, FRCP(C), MHScScientist, Ottawa Hospital Research Institute
Associate Professor, University of OttawaDepartment of Epidemiology and Community Medicine
Centre for Transfusion Research
CCCF, Toronto, Ontario, November 1, 2014
My talk for today
• Frame the potential future of immunotherapy using mesenchymal stromal cells for sepsis as the paradigm
• Discuss rationale/evidence for MSCs in sepsis
• Discuss past trial failures to help future successful translation
• Challenges and opportunities
• Trials coming down the pipes
Importance of severe sepsis/septic shock
• A major cause of morbidity and mortality worldwide – In the United States:• 2% of all hospital admissions• Leading cause of death in non-coronary ICUs• 10th leading cause of death overall • Mortality rates 20-40%• Estimated costs in USA: $17 billion annually
Angus et al, CCM: 2001, Alberti et al, ICM: 2002, Martin et al, NEJM: 2003;Levy, MM CCM, 2010: 38(2); 367-374; Kaukonen, KM, JAMA, 2014: 311(13: 1308-1316
Why Consider MSCs for Septic Shock?
MSCs and potential
mechanisms
Immune modulation
Mitochondrial function
Vascular permeability
Pathogen clearance
Immune priveledged
Minimal engraftment
Molecular phenotype of MSC-treated septic mice (CLP/MSCs) resembles that of normal mice (Sham/saline)
Mei and Haitsma et al AJRCCM, 2010; 182: 1047-1057
MSC treatment in septic mice caused•An overall down-regulation of inflammation-related genes•Up-regulation of genes involved in promoting antigen presentation, phagocytosis, and bacteria killing
MSCs represent an especially attractive potential
therapeutic for the treatment of sepsis since the
cells target many pathways
dos Santos, C et al, Am J Path, 2012; 181(5): 1681-92
Network Analysis of Transcriptional Responses Induced by MSCs
• Instilled mouse airways with LPS
• Administered mouse bone marrow MSCs intratracheally
• MSCs formed gapped junctional channels with alveolar epithelia
• MSCs released mitochondrial microvesicles that were engulfed by alveolar epithelium
• Post mitochondrial transfer, increase alveolar ATP concentrations
• Increased mouse surfactant secretion
M Islam et al, Nature Medicine, 2012; 18(5): 759 – 765
Rationale for MSCs in Sepsis: Mitochondrial transfer
MSCs mechanisms:Effects on lung permeability
• Ex vivo perfused human lung
• Intrabronchial installation of LPS into distal airspaces of the lung to induce acute lung injury
• Intrabronchial installation of allogeneic human MSCs or MSC conditioned medium given 1 hour post LPS challenge
Lee, JW et al, PNAS, 2009; 106(38): 16357-16362
Lung Histology Sections
Endothelial Permeability Lung Water
Overall Mortality: Pre-Clinical MSC Sepsis Experiments
McIntyre et al, preliminary unpublished dataOR < 1 favors MSCs as compared to controls
CFU Blood 0.64 (0.47,0.87)>6 to ≤24 5
0.64 (0.25,1.61)>24 to ≤48 1
CFU Peritoneum 0.82 (0.65,1.02)>6 to ≤24 4
0.66 (0.44,0.99)>24 to ≤48 1
CFU Spleen 0.42 (0.26,0.69)>6 to ≤24 2
0.2 (0.03,1.26)>24 to ≤48 1
0.01 0.1 1 10
Outcome Time (hrs)
Ratio of the Means (95% CI)
Number of Expts.Outcome
Pathogen Clearance: Colony Forming Units
Favours MSC Favours Control
McIntyre et al, preliminary unpublished dataRoM < 1 favors MSCs as compared to controls
Creatinine 1 (0.51,1.97)≤6 10.87 (0.72,1.04)>6 to ≤24 40.64 (0.51,0.82)>24 to ≤48 21.03 (0.9,1.17)>48 to ≤72 2
Pulmonary neutrophils 0.66 (0.48,0.89)≤6 1
0.71 (0.49,1.02)>6 to ≤24 30.55 (0.34,0.89)>24 to ≤48 10.61 (0.46,0.79)>48 to ≤72 20.46 (0.37,0.56)>72 to ≤168 2
Pulmonary MPO 0.77 (0.51,1.15)≤6 3
0.75 (0.47,1.18)>6 to ≤24 30.85 (0.71,1.03)>24 to ≤48 10.92 (0.85,0.99)>72 to ≤168 1
0.1 1 10
Outcome Time (hrs)
RoM < 1 favors MSCs as compared to controls
Ratio of the Means (95% CI)
Number of Expts.Outcome
Surrogate Organ Functions
Favours MSC Favours Control
> 100 Phase II and III clinical sepsis trials with little to no successful translation
Supportive Care remains mainstay of therapy
? Understanding pathophysiology? Clinical trial design
? Pre-clinical evidence
Marshall, JC, Trends in Mol Med, 2014; 20(4): 195-203
Sepsis is incredibly complex….and clinical trial design is challenging…..
Pathogen Factors• Type
• Load
• Virulence
• Molecular patterns
Host Factors• Genetics
• Age and Morbidities
• Medications
• Severity of Illness
Interventions/Co-interventions
• Timing/dose/duration of treatment
• Co-interventions
Angus, DC, NEJM, 2013; 369(9); 840-851
Outcomes• Surrogate outcomes
• Clinical outcomes
• Patient centred outcomes
Group Subgroup Experiments (n = 34)No (%)
Timing of MSC Administration
≤1 h>1 to ≤ 6 h> 6 hMultipleUnclear
15 (44)6 (18)4 (12)5 (15)4 (12)
Resuscitation Antibiotics and Fluid 3/16 (19)Cochrane risk of bias 25 studies
RandomizationAllocation ConcealmentBlinding personnelBlinding of any outcome
25/25 unclear25/25 unclear
23/25 unclear (2 low)13/25 unclear (12 low)
*Exceeds 100% due to multiple arm for a given experiment McIntyre et al, preliminary unpublished data
Characteristic Sub-Category # Expts DeathSummary OR (95% CI)
Resuscitation Fluids and Antibiotics
2 0.18 (0.08-0.42)
None 6 0.28 (0.13 – 0.60)
MSC Timing ≤ 1 hour 6 0.20 (0.12 – 0.35)
1 – 6 hours 6 0.30 (0.17 – 0.52)
> 6 hours 1 0.29 (0.08 – 1.06)
McIntyre et al, preliminary unpublished dataOR < 1 favors MSCs as compared to controls
Challenges and Opportunities Related to MSCs as a Potential Therapeutic….
• MSC characterization• MSC functionality/potency
• MSC acquisition• MSC source• MSC manufacturing• Fresh versus cryopreserved
• To stimulate or not?• Conditioned medium/exosomes
2 MSC ARDS Clinical trials
Design # Centres
Population/Sample Size
Intervention and Control
Outcomes
Zheng2014
RCTDouble Blind
Single ARDSN = 12
Allogeneic human adipose derived MSCs frozen/thawed/cultured(purchased from ATCC) 1 X 106 cells/kg
VS
Placebo
Primary: safety
Secondary: P/F ratio, Hospital LOS, ICU and ventilatory free days at day 28, serum biomarkers (Il-6, Il-8, SP-D)
Matthay(NCT01775774)
Phase I Dose escalation trial
Multi-centre
ARDSN = 9
Allogeneic human bone marrow derived MSCs1, 5, and 10 X 106 cells/kg
Primary: safety
Neither of these trials had any transfusion associated serious adverse events
CISS Trial Design• Design: Phase I single centre, open label safety and dose
escalation trial of MSCs in septic shock
• Primary Objective: • Determine the safety profile of MSCs in septic shock • Determine the maximum tolerable dose of MSCs in septic shock
• Secondary Objectives: • Examine biological effects of MSCs through measurement of serial
biomarkers of inflammation and acute phase proteins
• Examine measures of feasibility related to trial implementation and conduct
In Summary….my thoughts on whether there is a future for cellular therapy trials• Better understanding of sepsis pathophysiology• Efforts for better clinical trial designs • More robust pre-clinical evidence but still much to learn
Translational and Clinical Scientists