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ImmunologicalFactorsforEndometriosis:TheClinicalImplications
Christian Becker University of Oxford
Consultancy: ObsEva(IDDM)
Researchgrants: Bayer
RocheDiagnostics
MDNALifesciences
Conflict of interest
Nisolle M & Donnez J, Fertil Steril 1997
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Reference npatients AFSStage Progression Stable Regression
Thomas,1987 17 I-II 8 0 9
Telimaa,1987 12 I 3 8 1
Mahmood,1990 11 I-III 7 1 3
Overton,1994 15 I-II 4 3 8
Sutton,1994 24 I-III 7 10 7
Harrison,2000 43 I-IV 4 12 27
Abbott,2004 18 II-IV 8 6 4
TOTAL 140 41(29%) 40(29%) 59(42%)
Modified from Evers JLH, Hum Repord 2013
Natural course of disease
Clinicalimplicationsofimmunefactorsinendometriosis
Pathogenesis Biomarkers
Symptoms Treatments
➔ Screening
➔ Patientstratification
➔ Indicatoroftreatmentresponse
➔ Courseofdisease
➔ Riskofrecurrence
Applications for biomarkers
May et al., Hum Reprod Update 2010
Working Group D. Adamson, R. Anchan, G. Buck-Louis, K. Chwalisz, T. D’Hooghe,
A. Fassbender, T. Faustmann, L. Giudice, M. Laufer, G. Montgomery, N. Rahmioglu, P. Rogers, P. Stratton, S. Tworoger, P. Vigano, A. Vitonis
EPHect Study
Extended Working Group
Harvard Stacey Missmer
University of Oxford Krina Zondervan Christian Becker
Lone Hummelshoj
FertilSteril,2014
Endometriosis Centres currently using WERF EPHect tools
http://endometriosisfoundation.org/ephect/
Clinicalimplicationsofimmunefactorsinendometriosis
Pathogenesis Biomarkers
Symptoms Treatments
Patients
Pain Infertility
Fatigue
Berkley KJ et al., Science 2004 Tokushige et al., Hum Reprod 2006
Peripheral nerve fibres
De-regulation of peripheral autonomic nerve system in endometriosis
IncreaseofsensorynervefibresLossofsympatheticnervefibres
(Arnold J et al, Brain Behavious and Immunity 2013)
Morotti M et al, Hum Reprod Update 2014
Tracey I & Mantyh PW, Neuron 2007
Clinicalimplicationsofimmunefactorsinendometriosis
Pathogenesis Biomarkers
Symptoms Treatments
Wong et al., 2009
Pain improvement with COCP
FavorsPlacebo FavorsCOPC
Becker CM et al., Fertil Steril 2017
Response to medical therapy - Symptom recurrence after treatment cessation -
No reduction in symptoms
Pain symptom remaining at end of treatment
Recurrence of symptoms after treatment cessation
Jacobson et al., 2010
Pain improvement after laparoscopy
FavorsNoSurgery FavorsSurgery
No reduction in pain symptoms
Persistence of pain symptoms remaining after
surgery
Recurrent symptoms
Recurrent surgery
Change in VAS score from
baseline (cm)
AEs (AEs/ women)
Diagnostic surgery
77.4% ND ND 77.4% +0.3 0/31
Lesion excision11.8%
(3.6–22.2%)25.0%
(4.4–41.7%)15.8%
(0.0–42.0%)22.6
(5.8–56.9%)–3.6 124/1527
Lesion ablation 11.4% ND ND ND –2.4 0/79
Endometrioma drainage only
ND ND54.8
(52.9–75.0%)51.5%
(22.9–80.0%)ND 0/32
Pelvic denervation
6.7% (5.8–15.0%)
34.3% (8.6–48.1%)
28.7% (10.0–36.0%)
12.5% –2.2 27/182
Hysterectomy with ovarian preservation
ND ND ND 19.1% ND ND
Hysterectomy without ovarian preservation
ND ND ND 8.0% ND ND
DIE0.0%
(0.0–4.4%)2.3%
(2.2–4.4%)7.0%
4.1% (1.3–27.6%)
–6.2 63/779
Response to surgical therapy - Main outcome measures -
Singh S et al., submitted
Recurrence rate of endometriosis after surgical treatment
5 years 40 - 50%
2 years 21.5%
Guo SW, Hum Reprod Update 2009
Current/future immune targets to endometriosis
TNF-α in endometriosis
• Pro-inflammatory cytokine
• Produced by activated macrophages and endometriosis lesions
• Induces IL-8 production by peritoneal mesothelial cells
• Up-regulated in peritoneal fluid of endometriosis patients
• Levels correlated with stage of disease
• Possible Mechanisms: Stromal cell adhesion and proliferation ECM degradation and invasion Inhibition of embryo development in rodents
Monoclonal antibodies (Infliximab)
Baboons (c5N)
Inhibition of endometriosis
↓
Human study
Soluble TNF-α receptors (r-hTBP-1)
Rodents
Inhibition of implants
Baboons
Inhibition of development and growth of endometriosis
↓
No human study
TNF receptor fusion protein (Etanercept)
↓
No human study
Nopainstudiesinanimals
Blockage of TNF-α In vivo studies
21 women with rectovaginal endometriosis
Infliximab (n= 13) Placebo (n = 7)
40 weeks ↓
4 weeks observation ↓
12 weeks treatment ↓
Surgery ↓
24 weeks follow-up
Start of Menses
2 weeks
6 weeks
Koninckx PR et al, Hum Reprod 2008
Blockage of TNF - α RCT study outline
• Single centre, randomized, double-blind, placebo- controlled pilot study
• NCT 00604864 (Phase II trial)
• Primary outcome: Change in pelvic pain including use of analgesics (Biberoglu/ Behrman, VAS)
• Secondary outcomes: Volume change of rectovaginal nodules (clinically/TVU)
Appearance of nodules (surgery)
Extent of disease (surgery)
Koninckx PR et al, Hum Reprod 2008
Blockage of TNF - α (RCT) Study outcomes
Koninckx PR et al, Hum Reprod 2008
Blockage of TNF - α (RCT) Study results
Koninckx PR et al, Hum Reprod 2008
Blockage of TNF - α (RCT) Study conclusions
Pain severity decreased by 30% in both groups
No effect of Infliximab in any of the outcome measures
Surgery improved pain scores to < 20% in both groups
Pentoxifylline
Methylxanthine inhibiting phosphodiesterase
Usually used to improve blood flow
May induce sperm motility
Has anti-inflammatory effects Inhibits TNF production in vitro
Reduces action of TNF and IL-1 on neutrophils
Inhibits phagocytosis and production of ROS from macrophages and neutrophils
Pentoxifylline in endometriosis Cochrane review - Background
Lu D et al., Cochrane Database Syst Rev, 2012
Four studies with total 334 patients included
Intervention: Pentoxifylline 800 mg qd after laparoscopy
Comparator: Placebo (3 studies)
Study length: 3-12 months
Outcomes: Pain relief (VAS; 1 study)
Clinical pregnancy rates (3 studies)
Recurrent rate (1 study)
Lu D et al., Cochrane Database Syst Rev, 2012
Primary outcome: Pain reduction
Secondary outcome: Clinical pregnancy
Secondary outcome: Recurrence rate
Pentoxifylline in endometriosis Cochrane review - Results
Pentoxifylline in endometriosis Cochrane review - Conclusions
Lu D et al., Cochrane Database Syst Rev, 2012
Overall poor study quality: - no LBR recorded
- no non-pain related endometriosis-associated symptoms recorded
- no adverse events recorded
- no intention-to-treat approach
- allocation concealment in two studies recorded
- double blinding in three studies
- different stages of endometriosis included in different studies
Not enough evidence to support the use of pentoxifylline in endometriosis for subfertility or relief in pain outcomes
PPAR-γ in endometriosis
• Peroxisome proliferator-activated receptor γ
• Nuclear receptors usually activated by free fatty acids , eicosanoids
• Activation of PPAR-γ: Inhibits macrophage activation and cytokine
production of monocytes Antiangiogenic
Inhibits endometrial cell proliferation
Antiestrogenic properties
• PPAR-γ is expressed in endometriotic stromal cells
• Correlation between PPAR-γ expression and pain scores
PPAR-γ in endometriosis
Baboon model Surgically induced endometriosis 1 month treatment
Controls n = 6
Pioglitazone n = 6
Lebovic D et al., Endocrinology 2010
PPAR-γ in endometriosis
Baboon model
Lebovic D et al., Endocrinology 2010
• Single centre study, placebo controlled study
• NCT 01184144 (Phase 2)
• Primary outcome: Difference in soluble pro-inflammatory markers in peritoneal fluid
• Status: Withdrawn
→ Other studies have been withdrawn due to cardiovascular risk (rosiglitazone)
PPAR-γ ligand pioglitazone Human study
Source: clinicaltrials.gov
Ancién P et al., Fertil Steril, 2002
Rationale: Enhancement of cytotoxic activity of macrophages and NK cells Reduction in experimental endometriosis in rodents
Study: Single centre, open-label RCT
Intervention: Conservative open surgery +/- intraperitoneal IFα-2b or placebo +/- postoperative GnRHa or Indomethacin
Second-look laparoscopy after 9-12 months
Primary outcome: Recurrence of endometriosis at 2nd look laparoscopy
Secondary outcomes: CA125 levels Lymphocyte populations Immunoglobulin levels
Interferon α-2b
Ancién P et al., Fertil Steril, 2002
Interferon α-2b Study profile
Ancién P et al., Fertil Steril, 2002
Interferon α-2b Results
Interferon α-2b Conclusions
Ancién P et al., Fertil Steril, 2002
Intraperitoneal IF α-2b after conservative surgery increases recurrence rates of ovarian endometriosis
No change in lymphocyte or IG levels
Rationale: Triggers NK cells activation by T cells Activates growth and expansion of T lymphocytes Causes cytolysis of aberrant ectopic cell in vitro Reduction in experimental endometriosis in rodents
Study: Single centre, double-blinded RCT
Intervention: 3 months GnRHa + 1x transvaginal drainage of endometrioma +/- intra-cystic injection of 1x 600,000 IU rIL-2 or placebo
Primary outcomes: Changes in pain scores (VAS) Endometrioma size change CA125 levels
Secondary outcome: Time to pregnancy
Interleukin – 2 Background
Ancién P et al., Gynaecol Obstet Invest, 2003
Ancién P et al., Gynaecol Obstet Invest, 2003
Interleukin – 2 Conclusions
Recurrence of endometriomas similar in both groups
rIL-2 group: Prolonged period until recurrence
Lower VAS scores
Fewer cases with increased CA125
Fewer surgeries necessary (n.s.)
Very small study
Ancién P et al., Gynaecol Obstet Invest, 2003
V-Endo
• Open-label, one arm immunotherapy for 2 months, phase 1
• NCT 03340324
• Primary outcome: Change in pelvic pain (VAS) over 2 months
• Secondary outcomes: Quality of life changes Effect on liver and kidney parameters and FBC
• V-Endo is a tableted immunotherapeutic derived from hydrolyzed, heat-inactivated, pooled blood from women with endometriosis
• Location: Mongolia
IRAK
IL-1 receptor-associated kinases
Regulating expression of inflammatory genes in immune cells
Critical for elimination of bacteria, viruses, cancer cells
IRAK-4 is the central member
IRAK-4 Inhibitors
Boher RN et al, AACR 2017
IRAK-4 Inhibitor in cancer
Boher RN et al, AACR 2017
Current/future immune targets to endometriosis
Clinicaltrials.gov ↓
Endometriosis (n = 306)
Not yet recruiting (12) Recruiting (57) Enrolling by invitation (6) Active, not recruiting (17)
Suspended (4) Terminated (13) Withdrawn (12)
Completed (140)
With Results (13)
Without Results (127)
Unknown(45)
Future prospects
Lesion Colour
Lesion Location
Pain Quality Infertility
Genetics
Molecular Markers
Co- Morbidities History
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Source:ManchesterPrecisionMedicineInstitute
Stratified and precision medicine
TNF-α
Esposito E & Cuzzocrea S, Trends Pharmacol Sci, 2011
Ancién P et al., Gynaecol Obstet Invest, 2003
Interleukin – 2 Results
EvaluationofM1andM2MacrophagesinEndometrioticTissueofWomenAffectedbyEndometriosisatDifferentStages.NCT03136978
OpenLabelImmunotherapyofEndometriosisNCT03340324
DoesImmunotherapyHaveaRoleintheManagementofEndometriosis?NCT03464799
Endometriosis:ImmunomodulationNCT01184144
EffectofRosiglitazoneonPeritonealCytokinesinWomenWithEndometriosisNCT00121953
EffectofAntiTNFaUponDeepEndometriosisAssociatedPain(Infliximab)NCT00604864
PGL5001ProofofConceptStudyinInflammatoryEndometriosis(JADE)NCT01630252
StudytoInvestigatetheEfficacyofaNon-hormonalDrugAgainstEndometriosisAssociatedPelvicPainNCT00185341
PentoxifyllineandEndometriosis(LETS1)NCT00632697
Attributes of ideal biomarkers
Cheap
Robust
Reliable Replicable
Validated
Relevant
Sensitive Specific
Accessible
Simple
