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

Disclosures

• Nothing to disclose

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

Angus, DC, NEJM, 2013; 369(9); 840-851

Hotchkiss, RS, Nature Reviews, 2013; 13: 862-874

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

Ann Am Thorac Soc, 2014; 11(5): 728-736

PLoS ONE, 2014; 9(1):e86242

Can we improve on the pre-clinical evidence?

SYSTEMATIC REVIEW AND META-ANALYSIS OF MESENCHYMAL STROMAL CELLS IN PRECLINICAL MODELS OF SEPSIS

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

CELLULAR IMMUNOTHERAPY FOR SEPTIC SHOCK: CISS Trial

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

My Disclaimer

MSCs and potential dual role in inflammation…….

Monsel, A et al, Anesthesiology, 2014; 121: 1099-1121